Accumulating evidence suggests that non-invasive and invasive brain stimulation may reduce food craving and calorie consumption rendering these techniques potential treatment options for obesity. Non-invasive transcranial direct current stimulation (tDCS) or repetitive transcranial magnet stimulation (rTMS) are used to modulate activity in superficially located executive control regions, such as the dorsolateral prefrontal cortex (DLPFC). Modulation of the DLPFC’s activity may alter executive functioning and food reward processing in interconnected dopamine-rich regions such as the striatum or orbitofrontal cortex. Modulation of reward processing can also be achieved by invasive deep brain stimulation (DBS) targeting the nucleus accumbens. Another target for DBS is the lateral hypothalamic area potentially leading to improved energy expenditure. To date, available evidence is, however, restricted to few exceptional cases of morbid obesity. The vagal nerve plays a crucial role in signaling the homeostatic demand to the brain. Invasive or non-invasive vagal nerve stimulation (VNS) is thus assumed to reduce appetite, rendering VNS another possible treatment option for obesity. Based on currently available evidence, the U.S. Food and Drug Administration recently approved VNS for the treatment of obesity. This review summarizes scientific evidence regarding these techniques’ efficacy in modulating food craving and calorie intake. It is time for large controlled clinical trials that are necessary to translate currently available research discoveries into patient care. Obesity and associated comorbidities such as cardiovascular and endocrinological diseases as well as cancer and dementia are spreading worldwide reaching a pandemic level . ObesityIn the following, I first introduce brain sites representing potential target regions for non-invasive and invasive brain stimulation. I highlight their functional role in energy homeostasis, food hedonism, food choices and obesity. Next, I introduce different non-invasive and invasive brain stimulation techniques before I summarize and discuss available evidence on their effectiveness in modulating food craving and calorie consumption in obesity.Homeostasis describes the evolutionary founded energy balance between ingestion and consumption. During fasting, hunger-signaling pathways trigger augmented attention to food cues and sensitivity to food-related rewarding stimuli. During consumption, the food’s taste and texture enter our awareness via the tractus solitarius in the brainstem, from which projections through the thalamus reach taste-associated neurons in the insular cortex and its frontal operculum . The incEating for pleasure can elicit food consumption without hunger and beyond satiety. Hedonic brain systems, including the nucleus accumbens, the dorsal striatum, the ventral tegmental area and orbitofrontal cortex (OFC), assess the food’s rewarding properties .The nucleus accumbens, as part of the ventral striatum, is a dopamine rich area that subserves motivation, reward and reinforcement learning . Hence, The dorsal striatum is active during the consumption of food and its devaluation when eating beyond satiety . Its conThe OFC merges gustatory input from the insula with cognitive information as well as incentive value from the limbic system, enabling a subjective rating of food . StudiesObese individuals share certain behavioral pattern with drug addicts, such as craving, probably related to cue-associated enhanced activity in reward-associated brain regions . During Also, the OFC seems to play a role in the development of obesity. Its medio-caudal part was found to be structurally altered in relation to an increased body weight  and its Reward-related brain systems are permanently interacting with the hypothalamus to guarantee energy homeostasis. Living in an environment of constant availability of high-caloric food, these closely linked systems can become independent and hedonism overpowers homeostasis. Individuals may consume food beyond satiety based on the interplay of food cues emerging of an obesogenic environment and personal traits, such as ‘neuroticism,’ ‘impulsivity’ and ‘sensitivity to reward’ , that inThe dorsolateral prefrontal cortex (DLPFC) was shown to be involved in self-control  and cognThe involvement of the DLPFC in food choices is supported by body weight related structural  and funcThe two most popular non-invasive brain stimulation techniques are repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). Due to their restricted penetration depth, both techniques can be used to target superficially localized brain areas, such as the DLPFC or the frontal operculum/insular cortex. RTMS or tDCS applied to those regions may modulate activity also at interconnected distant brain sites, but these effects are not well investigated.The stimulation of homeostatic  or hedonic brain areas  requires non-invasive/invasive vagal nerve stimulation (VNS) or invasive deep brain stimulation (DBS). These techniques will be introduced after tDCS and rTMS.tDCS is a safe method to deliver subliminal tonic currents through two surface electrodes (anode and cathode) fixed to the head . The curDelivered to the primary motor cortex, TDCS modifies cortical excitability in a polarity-specific manner . Anodal For sham tDCS, the current is temporarily ramped up and then ramped down again, avoiding longer active brain stimulation. With this procedure, participants experience the same tingling sensations that occur during the first few minutes of real tDCS .The TMS coil that contains a magnetic field generator is fixed to the head over the brain site of interest. The magnetic field elicits a small electric current in the targeted cortical assemblies via electromagnetic induction. Low frequency rTMS  delivered to the primary motor cortex attenuates cortical excitability without affecting cortical inhibition. High frequency rTMS (≤5 Hz), in turn, leads to an attenuation of cortical inhibition . Theta-bDuring motor cortex stimulation, the TMS effect can be easily captured via simultaneously recorded motor evoked potentials of the muscle whose representation falls into the stimulated cortical motor representation. The navigation of the TMS coil over brain regions without such a direct output, e.g., the DLPFC, is more challenging and may be guided by neuro-navigation based on structural and/or functional CT/MRI of the participant’s brain.The vagal nerve is a peripheral nerve that belongs to the autonomic nervous system. It is linked to parasympathetic control of the heart, lungs, and digestive tract. It also has a sympathetic function via peripheral chemoreceptors. For clinical purposes, stimulation of the vagal nerve is used to treat drug-refractory epilepsy and treatment-refractory depression .The vagal nerve receives afferent inputs from the stomach and is involved in signaling the homeostatic feedback to the brain. Its invasive or non-invasive stimulation is thought to reduce appetite. Non-invasive VNS for such purposes involves transcutaneous stimulation of the T6 dermatome, and hence of afferent projections to the vagal nerve.For invasive treatment of obesity, the surgeon implants a helical coil at the abdominal trunk of the nerve proximal to the stomach. The small electric generator is implanted subcutaneously below the clavicle . The stiDeep brain stimulation demands the stereotactic implantation of electrodes in deep brain structures, whereas the pulse generator is implanted subcutaneously . DeliverElectrode implantation is done under local or generalized anesthesia, with or without electrophysiological recordings, and with or without perioperative psychological and neurological tests . DBS is For the treatment of obesity, DBS electrodes are implanted to the lateral hypothalamus area or the nucleus accumbens to modify homeostatic or hedonic food responses, respectively. So far, available data suggest that the stimulation of the lateral hypothalamic area could increase resting energy expenditure, while stimulation of the nucleus accumbens may reduce food intake . The mectDCS can be used to target superficially located brain regions, such as the DLPFC – the preferred target for non-invasive brain stimulation in obesity research. In most studies, one stimulation electrode is fixed to the right forehead , while the other electrode to the left forehead . For the inverse polarity anode and cathode are simply reversed.Previous studies accumulated evidence of an obesity-associated prefrontal imbalance  with dysBased on these assumptions, a number of studies investigating the effect of a single session of bilateral tDCS to the DLPFC. Accumulating evidence suggest that a single session of tDCS delivered to the DLPFC in lean individuals reduces food craving immediate to tDCS .Most pilot studies to date investigated the effect of a single tDCS session in small populations limiting their suitability to derive hypotheses for larger clinical trials with repetitive tDCS. To this end, tDCS’s influences on the DLPFC, associated cognitive effects as well as biochemical action mechanism must be further deciphered.Regarding tDCS’s biochemical action mechanisms in the rat brain, tDCS studies using either single session or repetitive sessions, support the assumption of a prefrontal imbalance, however not only in obesity , but alsBased on this evidence, Contrarily to these findings, tDCS applied to both DLPFCs showed an effect on food craving and calorie consumption . This efOnly few studies to date probed repetitive application of tDCS sessions on food craving and/or food consumption. Gluck et al. showed in a small, solely obese, mixed-gender human cohort that repetitive applications of anodal as compared to cathodal tDCS delivered to the right DLPFC resulted in reduced calorie consumption and greater weight loss .More recently, Also, More pilot studies with repetitive tDCS sessions, like the one by Like tDCS, rTMS is limited by its penetration depth, allowing the stimulation only of superficially located brain areas, such as the DLPFC. Stimulating the DLPFC with rTMS, however, elicits changes not only of the DLPFC’s activity but also of the muscles directly underneath the TMS coil. These contractions can be awkward, and they are difficult to mimic during sham stimulation.The advantage of rTMS is that it requires only a single stimulation coil and not two electrodes like tDCS. This allows to target brain regions with higher spatial accuracy. RTMS at high frequencies has the potential to facilitate activity in the targeted DLPFC, while simultaneously inhibiting activity in connected regions such as the OFC and the anterior cingulate cortex .Previous studies suggest that rTMS may have a treatment effect in addiction and possibly also in obesity, if obesity is associated with symptoms of food addiction . AddictiBrain imaging in food addicts revealed enhanced activation in the anterior cingulate cortex, medial OFC, and amygdala in response to anticipated receipt of food . Higher Accumulating evidence suggests that rTMS influences food craving and consumption even in obese individuals who do not suffer from food addiction (see Supplementary Table Although these findings agree with studies that investigated the effects of a single tDCS session (see “Effects of non-invasive tDCS”), they disagree with other rTMS findings again obtained from a small human cohort consisting solely of lean-to-obese women : In the Reduced food craving, nevertheless, seems to represent the best reproduced DLPFC-rTMS effect in obese individuals. Previous studies have shown that this effect can last for up to 2 weeks .Accumulating evidence from above-mentioned studies suggest that facilitatory high-frequency  rTMS applied to the left DLPFC reduces food cravings as well as food consumption if individuals receive multiple rTMS sessions. This assumption would be indirectly strengthened, if inhibitory rTMS provokes the inverse effect. One study recently addressed this question. The vagal nerve sends afferent signals from the stomach to homeostatic brain sites. Its non-invasive and invasive stimulation is therefore assumed to reduce appetite and body weight. Based on these assumptions, non-invasive VNS was supposed as a treatment option for obesity . First fIn a well-controlled proof-of-concept study, In agreement with these positive effects of non-invasive VNS, also invasive VNS has shown promising results in human studies. Findings of the so-called ReCharge trial suggest positive effects on appetite and body weight control . The ReCThese findings were corroborated by the VBLOC DM2 study. Intermittent invasive VNS among 28 obese individuals with type 2 diabetes mellitus over 2 years proved to be a safe procedure leading not only to weight loss but also to reductions of metabolic and vascular risk factors .There are two potential targets for DBS. One target is the lateral hypothalamus as the brain’s main homeostatic control site. The other one is the nucleus accumbens as a region of the hedonic brain circuitry underpinning motivation, reward and reinforcement learning. Converging evidence in rodents suggest that the shell and core of the nucleus accumbens are mediating reward-driven behaviors . DBS of Only few studies have investigated DBS effects in the obese human brain  or electric field strength (tDCS) remains unclear since most studies applied rTMS with potentially faciliatory protocols, such as 10 Hz, and tDCS with standard electric field strength, such as 2 mA over 20 min  and long-term depression (LTD) . LTP is In most prefrontal tDCS studies aiming at modulating food craving and consumption, one electrode is attached to the left forebrain and the other one to the right forebrain . That metDCS, in turn, evokes far less side effects . EspeciaIn face of possible therapeutic applications, tDCS bears a major advantage. It consists only of a battery and two (or more) electrodes . TMS devThe main limitation in the field of non-invasive DLPFC stimulation is the low number of randomized controlled studies, far more single session studies than multiple-session studies, a gender and age bias toward young females, and the lack of replication across stimulation techniques (see Table To assess their therapeutic potential, large clinical studies are required, like a recent study on depression that compared the effect of prefrontal tDCS plus antidepressant drugs versus antidepressant drugs alone . To studAs compared to tDCS and rTMS, far less evidence is available for the influence of DBS and VNS on food craving and calorie consumption (see Supplementary Table For VNS, few blinded and controlled clinical trials suggest that non-invasive  as well The translation of non-invasive and invasive brain stimulation techniques from laboratory settings to patient care would profit from large clinical trials, such as ReCharge  and VBLOBP searched the literature and wrote the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In this investigation, a wireless sensor network using a non-orthogonal multiple access (NOMA) system is considered in two scenarios related to the number of serving access point/base stations, where two policies provide system performance improvement in two sensors (the near user and the far user). To improve performance efficiency, two robust transmit antenna strategies are designed related to the access point/base station (BS), namely (i) Transmit Antenna Selection (TAS) mode and (ii) two base station (TBS) approach to simultaneously serve NOMA users. First, the TAS scheme is implemented to provide suboptimal outage performance for such NOMA, in which BS equipped at least two antennas while NOMA users are equippeda single antenna. Secondly, the TBS scheme is conducted to enhance the outage performance, especially considering priority evaluation for the far user in user pairs. As an important result, such far users in two proposed schemes are studied by introducing the exact closed-form expression to examine outage behavior. Accordingly, the closed-form expressions regarding ergodic capacity can be further obtained. To corroborate the exactness of these metrics, Monte Carlo simulation is performed. In addition, the proposed schemes exhibit various performance evaluations accompanied by different related parameters such as power allocation factors, the number of transmit antenna, and transmit signal-to-noise ratio (SNR). Towards fifth-generation 5G) wireless communication, mobile networks have attracted a huge amount of research with a major increase in recent years. First, spectral and energy efficiency are two folds of the enhancing system which aims to introduce strategy to fulfill 5G requirements and adapt fast speed in data transmission with thousand-fold higher rates ,2. SeconG wirelesRegarding the wireless channel, the sequence of the instantaneous channel gain or exact channel state information (CSI) at the transmitter side have been supposed in many of the recent works related to NOMA . HoweverDue to the flexibility and energy efficiency, wireless-powered relaying communication ,24,25,26At a glance, the first main contribution shows the advanced deployment of one/two base stations (access points) to serve destination users on the downlink in NOMA. This study proposes to jointly obtain the advantage of the superimposed signal and multiple access scheme to satisfy fairness data rate of the far user together with its improved outage performance.We show that the considered approaches effectively improve the far user’s outage behavior, which results from both transmit antenna selection decision regime and the cooperative NOMA scheme. However, the design of TAS (Scheme I) is a difficult task. To address such a disadvantage, Scheme II provides a simpler process than Scheme I but at least two nearby base stations (access points) are strictly acquired in the synchronization process at the receiver in Scheme II due to implement two BSs serving the far NOMA user in such case. Such nearby BS architecture is motivated by works in , or beamAs a third contribution, simulation and analytical results corroborate the exactness of our derived expressions and the advantage of NOMA. Furthermore, the outage performance in two schemes can be seen in opposite trends of the ergodic performance. In particular, Scheme I has better outage performance, while worse ergodic capacity can be achieved in Scheme I as compared with those in Scheme II.To provide a valuable benchmark, imperfect CSI is further studied, and degradation performance can worsen. The amount of channel error is controlled to maintain an acceptable outage performance. In most of the papers related to NOMA, two users are studied, but this paper further examines how system performance changes in scenarios where multiple users are served. The outage performance is further evaluated in Scheme III.In this investigation, motivated by novel results from ,21,28 weThe rest of this study is presented as follows. Notations: To simplify illustrations of expressions, X are represented as We consider cooperative Decode and Forward (DF) relaying network, where the base station (BS) communicates with two NOMA devices consisting of the near user and the far user by requiring the help of an intermediate relay ented in ,21 due tAs illustrated in i is selected on the BS for effective information transmission to User FU and User NU who follow the principle of NOMA transmission, but the FU needs higher priority in performance evaluation due to far distance. In particular, users with better channel conditions in NOMA obtain less transmit power while more transmit power goes to users with worse channel conditions to balance advantages of the system throughput and user fairness. Thus, users with better channel conditions required to decode the signals for the others before decoding their own and hence the optimal order for SIC is in the order of the increasing channel gain.As a main contribution, we determine the outage performance and ergodic capacity of NOMA relaying networks in the presence of one BS/two BSs approaches. Specifically, TAS and TBS techniques are exploited at the multi-antenna base station or two simultaneous serving BSs to enhance the quality of transmission employing NOMA. It is worth noting that the transmit antenna scheme requires selection combining (SC) for the receiver. In the proposed TBS, two BSs send superimposed signals to the User NU and the User FU at the same time and hence both NU and FU user must be able to combine signal from two links. To study system performance, we first derive several expressions of signal-to-noise ratio (SNR) and further investigate the outage behavior and ergodic capacity. More specifically, TAS scheme supposes that antenna Under NOMA scheme, the received signal based on observation of the selected antenna at User NU can be written asIn contrast with User NU, it is assumed that User FU can straight decode its information signal. The main reason to perform such an operation is that main signal in User FU is assigned with higher transmit power while the information signal of User NU produces the interference measured as noise. As a result, the received observation at User FU can be formulated byThen, the received SNR at User FU is given byBy employing DF scheme at NU, Lastly, User FU combines two signals using a selection combining (SC) technique from two links, i.e., the direct link in which signal is received from the BS and the relay link in which signal is received from User NU. Thus, the achievable SNR after combining signal in two links corresponding with two received signals at User FU can be formulated asThe end-to-end SNR to evaluate the received signal at the User FU is given byAs a result, such equation yields to simple expression asi the instantaneous rate obtained at User FU asIt is worth noting that regarding the complex constraint on It is noted that User NU has a shorter distance with the BS compared with User FU and hence K is the number of antennae at the BS in general case.A specific look on antenna criteria, to select an antenna that maximizes The following section introduces an exact expression for the outage probability considering on the whole range of SNR and arbitrary path loss factor for NOMA systems, with given power allocation coefficients in NOMA. Mathematically, the achievable end-to-end rate for User FU can be computed asProposition 1.The outage probability of the User FU achieved by the NOMA scheme, assuming given antenna selection, can be computed aswhere Proof. See in We first define the ergodic capacity of User FU as belowUsing Proposition 2.The ergodic capacity of the User FU achieved by the NOMA scheme, assuming given antenna selection, can be computed asProof. See in In this case, we consider the BS equipped two antennae. Due to imperfect CSI (ipCSI), the channel is measured with error component as belowThe received signal can be rewritten at User NU and User FU asThen, the SINR to detect Similarly, SINR can be computed at User FU asConsidering on relay link NU-FU, the received signal can be achieved at User FU in this link asThen, SNR can be calculated at User FU related to relay link asIn this step, outage performance is predicted that varying amount of performance happens due to impact of ipCSI term, it can be given asImpact of ipCSI results in computations of two components Substituting Equations  and 30)30) into This proposed TBS-based NOMA relaying network enhances the outage performance region by providing a downlink from two nearby BSs to simultaneous serve User NU, FU without requiring a complexity computation as antenna selection architecture in the previous section. In this scenario, two BSs transmit superimposed signals in downlink to the NU to perform signal processing at the NU due to low cost and complexity in system design. In this benchmark of TAS scheme, we compare TAS with a TBS to provide guidelines for practical design of NOMA scheme with improved outage performance. According to NOMA protocol, optimal power allocation factors including The received signal can be obtained at the User NU as belowSimilarly, the received signal at the User FU can be computed byWe assume that the two signals from two BS transmit to User FU in direct link in same time thanks to the required perfect synchronization operation required. It is assumed that FU can be able to detect its signal in the direct link while the NU first detects the FU’s signal and then further detects its own signal. Therefore, the received SINR at FU to detect information On the other hand, User NU performs SIC to decode symbols Then, the received SINR at User NU to identify own signal can be formulated byDuring the second phase, only User NU equipping the transmit power of In this section, we present the exact closed-form solution for outage probability over the two simultaneous transmit antenna at the BS with its required target rate. If both the direct link BS-FU and relaying link BS-NU-FU are unable to satisfy the predefined target data rate, outage behavior can be extracted from the proposed system. This study only focuses on outage performance of User FU and it is given byProposition 3.The outage probability in TBS-based NOMA mode can be computed aswhere Proof. We continue compute the components in expression of outage event as followPrminPPk≤m. TheBy exploiting statistics and binomial theorem , the PDFFinally, the outage performance of the m-th user can be evaluated byIn this section, numerical examples are presented to validate the outage performance of the downlink NOMA network under Rayleigh fading channels with two transmission policies. Moreover, system performance of NOMA is compared system performance in terms of outage and ergodic capacity performance with different parameters in such networks, where antenna transmit architecture is scheduled from derived expressions. The channel gains are set In In In This paper first considered real scenarios regarding NOMA users who are being served by two-antenna BS (Scheme I) or two single-antenna BS (Scheme II). Considering that the number of antennae has an impact on the gained SNR computation at destination, we have theoretically derived the outage probabilities of the far User FU. In Scheme II, two nearby BSs transmit a superimposed signal to the User NU to forward the signal to far User FU. Simulation results demonstrated that Scheme I has better outage probability compared with the others. In contrast, the ergodic capacity in Scheme II exhibited improved performance in comparison with that in Scheme I at several scenarios in the NOMA relaying system, and then helped choose which one was suitable for real implementation. Scheme III introduced the scenario of existence of multiple users in practice. It can be seen with each user having different channel condition results in different outage performance. In addition, with the metric of outage probability, we further evaluated ergodic capacity of such NOMA and theoretically derived ergodic performance, and two considered policies are examined. It is found that no matter which transmission policy is selected, the power allocation coefficients and transmit power at the BS are the main parameters affecting system performance in terms of outage behavior and ergodic capacity. These systems are suitable to implement wireless sensor networks where high demand of massive connections from sensors are satisfied. In future work, full multiple-antenna systems will be studied to provide further comparison related to these considered systems.


Chaim M. Bell and Lauren Lapointe-Shaw discuss the meaning of the "weekend effect" in outcomes for hospital admissions and surgeries, and comment on surprising new results published in PLOS Medicine this week. PLOS Medicine, O’Leary and colleagues compare the outcomes of weekend-admitted patients undergoing surgery with those of weekday-admitted patients [Who would have thought that outcomes for elective surgery would differ according to the day of admission? In this issue of patients . This stSince the weekend effect was first described, many have wondered whether it results from variation in care or simply differences in the risk profiles of weekend and weekday patients –4. MethoBecause of the importance of ensuring equity of care across all days of the week, tools to untangle patient and care effects are in continuous development. For example, excess risk over time curves have been used to identify conditions with an early-peaking risk, which could signal an acute weekend care–related effect. In contrast, a long period of increased risk may be a marker of a higher risk patient profile . AnotherDifferential admission patterns are thought to underlie the increased clinical severity of patients admitted to hospital on weekends . A highePatients undergoing surgery on weekends have been found, in some cases, to experience worse outcomes than those operated on weekdays. Notably, studies of elective procedures have identified a significant weekend effect  ,19, yet In the study reported in this issue, O’Leary and colleagues do an excellent job of examining the relationship between urgency of admission and the weekend effect for surgical patients. The association between weekend admission and slightly worse outcomes in the overall cohort can be explained by a large weekend effect for electively admitted patients. This may be greater for patients who undergo surgery on the weekend  than for those undergoing surgery on a subsequent weekday . In contrast, there was no weekend effect for urgently admitted patients, whether operated on the weekend  or on a subsequent weekday .That electively admitted weekend patients were at risk regardless of the timing of surgery is noteworthy. For those undergoing surgery on a weekday, the “weekend effect” experienced cannot be attributed to the quality of intra- and post-procedural care. Instead, it is only the preoperative care that could be reasonably reflective of weekend practices. As the authors astutely note, patients admitted electively over the weekend for surgery on a weekday may in fact be admitted for preoperative medical optimization. This would suggest that they are indeed at higher risk of a poor outcome after surgery, notwithstanding any optimization.For elective patients who undergo surgery on the weekend of admission, the increased risk could reflect the overall quality of care on weekends, for all aspects of pre-, intra-, and postoperative care. Alternatively, a weekend surgery in an electively admitted patient may signal that an elective procedure has now become urgent. One further consideration is that elective patients admitted on weekends are slightly more urgent than the average weekday elective patient. Because hospitals and operating rooms have lower occupancy on weekends, shifting an elective case to the weekend may be one way to shorten wait time for a patient whose condition is deteriorating on the wait list. Surgical admissions, although classified in binary manner as “urgent” or “elective,” may exist on the full spectrum of medical acuity.Previous research has indicated that, in many cases, weekend-admitted patients are sicker than weekday-admitted patients. Large differences in volumes and outcomes for weekend elective patients raise the possibility of confounding on the basis of patient risk profiles. The study by O’Leary and colleagues convincingly demonstrates a large weekend effect for weekend-admitted elective patients who subsequently undergo surgery. However, we need a better understanding of how elective weekend patients may be different. Otherwise, any implementation of widespread staffing or protocol changes would be premature.


Almost 600,000 patients are treated for alcohol abuse and alcohol dependence in the United States each year. Yet no one treatment approach has been shown to be successful for all these patients. Innovative treatment modalities are being studied in an effort to make alcoholism treatment more effective and more economical. It is estimated that 9.6 percent of men and 3.2 percent of women in the United States will become alcohol dependent at some time in their lives ; many moBoth alcohol dependence and alcohol abuse are disorders that can and should be treated. According to a 1991 survey of alcoholism and other drug abuse treatment facilities and their clients, almost 575,000 clients were treated in 8,928 facilities in the United States . Of thesThis overview describes current types and innovative components of alcoholism treatment and evidence of their effectiveness. In addition, treatment needs of priority populations,Alcoholism treatment services are delivered in two general settings—inpatient and outpatient. Inpatient settings mostly consist of short-term residential programs. They often are used for the early phases of treatment, particularly acute detoxification. Outpatient settings provide more long-term maintenance treatment, with group meetings and individual counseling offered once or twice a week. Because of current concern over increasing health care costs, more emphasis now is being placed on outpatient care during all stages of recovery. As a result, successful models of outpatient detoxification and intensive day treatment services have been developed.Residential 28-day treatment programs traditionally have been considered the foundation of the early recovery period. These programs often are based on the disease model of alcoholism and on the 12-step or Alcoholics Anonymous (AA) philosophy and practices. Abstinence from alcohol and other drugs (AOD’s) is the primary treatment goal in these programs. Patients participate in frequent AA meetings and ideally are linked to an AA sponsor and a local AA chapter prior to discharge.Inpatient settings, such as hospitals, provide intensive, highly structured treatment, such as group therapy and alcoholism education, for several hours daily. Issues covered in alcoholism education include health consequences, course of the disease, effects on the family, and other relevant topics. In addition to these group activities, clients work individually with a counselor to develop and implement a treatment plan that defines the treatment goals and to receive personalized therapy for special problems or needs. An essential element of residential programs appears to be milieu treatment, that is, living with a large number of alcoholic patients who have had similar experiences and problems and who can offer insight and advice on the recovery process. Professional staff are available during the treatment’s early stages to manage medical problems and to conduct a psychosocial evaluation to guide the treatment process. Toward the end of the hospitalization, treatment often involves the client’s family, and the spouse or other family members may be asked to join the treatment process.A recent study by In recent years, inpatient treatment programs have undergone substantial changes. For example, length of stay in many programs has decreased dramatically as a result of increased emphasis on outpatient interventions and of cost pressures from the insurance industry. Whether this affects treatment outcome has not been determined.The client population also has changed in recent years and now includes more multiple substance abusers than before. Consequently, the emphasis in many programs has shifted from a focus on alcoholism only to a focus on combined AOD dependence.The majority of alcoholic patients are treated on an outpatient basis. In 1991, 88 percent of the clients who sought treatment for alcohol problems were treated in outpatient facilities . These fIntensive outpatient programs were modeled after psychiatric day treatment programs, which emerged in the 1970’s as alternatives to inpatient hospitalization. The intensive outpatient programs vary considerably in the amount of time that patients are treated, ranging from 8 hours per day, 7 days per week, to 3 hours per day, several days per week. Several well-controlled studies comparing inpatient and intensive outpatient treatment have demonstrated comparable long-term outcomes but significantly lower costs in the intensive outpatient setting. For example, Intensive outpatient treatment may offer two kinds of advantages. First, it has clinical advantages by allowing patients to practice relapse prevention and management skills while being in a highly structured treatment setting. Second, it has practical advantages, such as the ability to serve larger numbers of patients; increased scheduling flexibility ; and an opportunity for the patients to maintain their established roles of employee, spouse, and/or parent while receiving intensive treatment.Regular outpatient alcoholism services are used as primary treatment or as extended aftercare following completion of an inpatient or intensive outpatient program. These types of outpatient services usually include weekly group therapy sessions, regular individual counseling sessions with an alcoholism counselor, participation in AA meetings, and family therapy when appropriate. The recommended treatment length generally is at least 1 year. The number of treatment sessions and the length of stay in outpatient treatment are related positively to long-term improvement in drinking behavior and other psychosocial areas .Outpatient programs can support and enhance the improvements achieved in inpatient treatment. In a study by Since the 1940’s community-based self-help programs have grown considerably. They are now widely available and offer an important intervention resource for people with alcohol problems. The best-known and most frequently used self-help program is AA. AA groups are self-governed and independent of formal alcoholism treatment facilities. Meetings are conducted by recovering alcoholics, without regard to formal counseling training and experience. Critical elements of the AA program include fellowship meetings, with members expected to attend 90 meetings in 90 days during the early recovery period; a sponsor system, in which newly recovering alcoholics are linked to an established member for assistance and advice; and the 12-step philosophy. This philosophy spells out a series of activities or steps that the alcoholic should achieve in the recovery process.It has been difficult to study AA’s effectiveness as a treatment intervention, in part because of the anonymity of AA members and in part because of the inability to conduct randomized clinical trials in an AA setting. One recent study found AA participation to be the only significant predictor of length of sobriety during long-term followup . Being aOften the first step of alcoholism treatment is managing the effects of abrupt cessation of alcohol intake through pharmacologically assisted detoxification. The majority of treatment components, however, strive to achieve long-term abstinence or reduced alcohol consumption in the patients. Recently, there has been increased emphasis on evaluating focused, standardized therapeutic interventions, which may be offered alone or as part of larger treatment programs. Components that show particular promise for effective treatment fall into two broad categories. One category consists of strategies to reduce alcohol use directly, such as brief interventions, pharmacotherapy, behavioral self-control training,Alcohol withdrawal can be a potentially life-threatening medical problem requiring medical care; however, fewer than 10 percent of alcohol-dependent patients are at risk for severe withdrawal symptoms. Thus, the challenge for cost-effective withdrawal management is to identify those patients who need pharmacological support and intensive medical care in an inpatient setting.®, Ativan®) are used widely for alcohol withdrawal management. Some investigators support benzodiazepine treatment for all patients with moderate-to-severe withdrawal symptoms because of possible long-term, cumulative central nervous system damage associated with repeated unmedicated alcohol withdrawal episodes, even if each episode seems innocuous  play a role in the development of alcohol consumption, tolerance, and dependence. Studies now are focusing on neuroregulating medications to reduce craving for alcohol and alcohol’s rewarding or intoxicating effects. One potential target is the opioid regulatory system. Two recent studies have reported that naltrexone, which blocks opiate receptor sites in the brain, decreases alcohol consumption and relapse in alcohol-dependent men enrolled in outpatient alcoholism treatment  and nonbenzodiazepine antianxiety drugs, such as buspirone. These drugs have known antidepressant properties and also decrease food and fluid consumption; either mechanism could decrease alcohol use. More recently, researchers have studied medications that reduce the uptake of the neurochemical serotonin Several strategies already are being used in clinical practice that attempt to match patients to existing treatment modalities more effectively. For example, Two research areas focus on the costs of alcoholism treatment. First, analyses of the cost-effectiveness of treatment compare costs and cost savings for treatment versus no treatment or among different treatment approaches. Second, studies of how alcoholism treatment should be financed compare public with private treatment settings and public with private insurance reimbursement systems.Research consistently has shown that alcoholism treatment reduces overall medical care costs of alcohol-dependent clients. One recent study demonstrated that over a 14-year followup period, health care costs for treated alcoholics were 24 percent lower than for untreated alcoholics . Only a Decisions regarding treatment setting are influenced strongly by pragmatic insurance coverage issues in addition to patient choice and treatment matching. For example, almost twice as many employees in insurance plans with more extensive inpatient coverage received inpatient care compared with employees whose plans had limited inpatient coverage . Such fiA study of national trends in alcoholism treatment during the late 1970’s and early 1980’s  suggestsThe treatment of alcohol abuse and alcohol dependence has benefited from a variety of scientific and clinical advancements in the last decade. There is growing evidence for the effectiveness of outpatient settings for the delivery of treatment services for alcoholics in all stages of recovery. New focused treatment interventions have been identified that are effective and that can be offered alone or as part of more comprehensive treatment programs. For example, pharmacotherapy and marital skills training show promise for decreasing alcohol use and relapse risk.Research on alcohol-dependent priority populations continues to highlight the unique problems and treatment needs of older persons, women, and minorities. Several studies provide encouraging evidence that treatment services addressing specific needs and emphasizing peer group participation can improve treatment outcomes for many patients. These findings lend further support to the importance of patient-treatment matching. An understanding of the interactions between specific patient, counselor, and treatment characteristics will yield the most successful long-term outcomes for all alcoholics. This information also will be critical in developing cost-effective financing and utilization management of alcoholism treatment in this country.


Thirty healthy infants will be enrolled as the control group. Maternal environment will be assessed via Emotional Availability Scales (EASs), with child responsiveness and maternal sensitivity as variables of interest. Infants’ scalp-recorded cortical activity in response to social and non-social stimuli will be investigated using a high-density EEG system (EGI Geodesic system). Neurodevelopment will be measured at 12 months of child’s life, using Bayley Scales for Infant Development (BSID), while the possible presence of emotional-behavioral problems will be rated via Child Behavior Checklist (CBCL). We expect that being IUGR significantly affects cognitive and behavioral outcomes, through mediation effects of both infants’ neural and behavioral capacity to respond to social stimuli. Indeed, we expect an altered response to social stimuli in IUGR infants, resulting in smaller ERP components amplitude in response to human faces compared to healthy matched peers. A significant association between neural response to social stimuli and infants’ responsiveness to maternal stimulation during interactions is expected, with impoverished performances on the interactive domain in IUGR, compared to healthy peers. This study will enhance understanding on neural mechanisms underpinning the interactive patterns sustaining socio-cognitive development in IUGR and healthy infants. The study will help in clarifying the role of postnatal environment in buffering the vulnerability experienced by children delayed in their fetal growth.Intrauterine growth restriction (IUGR) is defined as a fetal growth retardation, resulting in an estimated fetal weight less than the 10th centile for gestational age. IUGR developing brain is affected by the atypical fetal growth, presenting altered structure and connectivity and increased risk for neurodevelopmental impairments. Behaviorally, IUGR infants show reduced responsiveness and engagement with human faces during mother-child exchanges. The neural mechanisms of these patterns of interactions remain unexplored, as well as their potential role in shaping socio-cognitive trajectories of development. Aim of this research project will be to longitudinally investigate mother-infant interactions and infant’s event-related potential (ERP) components of face processing  in 4 and 9 months IUGR as potential early markers of expected atypical cognitive and behavioral outcomes observed at 12 months. Thirty IUGR participants will be recruited after receiving the  Intrauterine growth restriction (IUGR) is defined as a fetal growth retardation, resulting in an estimated fetal weight  on the lowest 10th percentile for gestational age , expecting IUGR lower levels of responsivity to maternal stimulation during free-play exchanges. Worse communicative abilities in the IUGR group can lead to an impoverished environment for the infant and therefore fewer opportunities for stimulation and learning. In turn, this could affect the cognitive development and therefore could represent a mechanism linking the stress experienced during intrauterine life to later adaptation.Infant neural social processing: many evidences showed that neural competence in face processing is significantly altered in clinical populations, advocating a likely role of this neural domain in sustaining and worsening the effects of early stress on child development. Since research on IUGR show their difficulties in engaging with faces and social situations, we suggest a potential role for face processing neural correlates in the association between antenatal growth restriction and cognitive outcomes. Therefore, we aim to explore the role of the scalp-recorded cortical activity, in terms of ERPs, in response to social and non-social stimuli in IUGR and non IUGR infants. The following ERP components will be selected in accordance with current evidence of the literature on infants’ face processing—i.e., the infant N170 at around 290 ms after the stimulus onset and P400  will be recruited from birth-preparation courses of the Obstetrics and Gynecological Clinic of Padua Hospital. All pregnant women are orally presented with a longitudinal study on the role of IUGR on child socio-emotional development by a Gynecologist and a Psychologist, while waiting their visit or the birth-preparation class. For mothers with pregnancy complicated by IUGR; research will be proposed at the first obstetrical visit following diagnosis. All mothers interested in the study will receive a detailed informative module, describing stages and tasks on the study. In particular, they will be informed on the study length and procedures; absence of risk for both behavioral and EEG assessment is declared, and a potential tolerable level of discomfort is reported for the EEG cup wearing procedure. Participants will also be informed on the possibility to withdraw their participation at any time without giving an explanation and that their decision would not affect future healthcare encounters. In accordance with the Declaration of Helsinki, prior to first assessment, parents agreeing to be involved in the present study will sign written informed consent. Mothers will sign an informed consent as participants; while two other different consent forms are required to be signed by both parents for infant’s participation, namely in the behavioral and neuroimaging assessments. The present study received ethical approval from the Ethic Committee of the University of Padua (protocol reference number: 2293).For the IUGR group, 30 pregnant women will be recruited at the Department of Women’s and Child’s Health, University of Padova . Healthy control pregnant mothers (in utero IUGR diagnosis (verified by Doppler ultrasound and estimated birth weight below the 10th percentile of growth), confirmed by birth weight below the 10th percentile of growth curve. Infants exclusion criteria will be: genetic disorders, unrelated comorbidities, presence of fetal infections, congenital malformations , metabolic and chromosomal disorders at birth, as well as infant neurological pathologies, brain abnormalities, or preterm delivery . Mothers’ exclusion criteria will be IUGR diagnosis before the 7th month of pregnancy and complicated pregnancies, non-Italian nationality, mother age <18 years, psychiatric disorders’ risk as defined by clinical score  in the Symptom Checklist 90-Revised —Short Form . For Cognitive, language and motor scales also allow to compute composite scores, referred to a mean value of 100 and a standard deviation of 15. Composite scores lower than 85 were considered as abnormal performances  through a pre-cabled high-density 128-channel HydroCel Geodesic Sensor Net (HCGSN-128) referenced to the vertex. While infants are placed on their mother’s legs in front of a screen at about 50 cm of distance, brain activity will be registered, through the use of the elastic sensor nets fitting each participant’s head size. Each electrode channel of the net is enveloped by a sponge and protected by a soft, plastic pedestal; this guarantee participants’ skin contact is only with sponge and plastic parts. Before assembly, Sensor Net is immersed in a shampoo, potassium chloride and distilled water solution for 5 min. After disassembly, all the non-disposable material used during the experiment , is always disinfected before a subsequent re-use.The electrophysiological data collection will last about 30 min per each infant, including equipment assembly and disassembly; also, to maximize infant comfort, skin pressure points and overturned sensors are checked before data acquisition, in accordance with EGI recommendations. While seating on mothers’ legs in the overshadowed room, both social and non-social stimuli will be presented. Specifically, the experimental paradigm employed will be adapted from a previous study  as between factor and developmental stage (4–9 months) and stimuli condition  as within factors. No previous study is available to obtain an estimate of the target effect size; however, we can refer to Parker and Nelson  work on Second, to test the mediation effect of both neural response to social stimuli and behavioral child responsiveness on cognitive and neurodevelopment outcomes, Hayes approach will be followed Hayes, . The powFor the developmental outcomes at 12 months, in line with previous studies , in line with previous studies on infants face processing  in order to identify differential trajectories starting form specific etiopathological conditions, or rather common mechanisms predisposing to multiple outcomes.In conclusion, very few is known on the effect of antenatal growth on socio-emotional development during early infancy. Studies investigating early pattern of social processing (Tronick and Beeghly, CS designed the study and drafted the manuscript. PDC contributed to the manuscript draft, planned the analyses, and performed the power analysis. GM designed the experimental tasks and revised the manuscript critically for important intellectual content. TF contributed to the design of the experimental tasks and revised the manuscript critically for important intellectual content. SV contributed to the study design. AS mentored the first author in designing the study, revised the manuscript critically for important intellectual content. All the authors carefully read and approved the final version of the manuscript.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.


Post-traumatic stress disorder (PTSD) is a psychiatric disorder associated with memories of traumatic experiences. Conditioned fear memory, a representative model of traumatic memories, is observed across species from lower to higher animals, including humans. Numerous studies have investigated the mechanisms of conditioned fear memory and have led to the identification of the underlying processes involved in fear memory regulation, including cellular and systems consolidation of fear conditioning, destabilization/reconsolidation and extinction after fear memory retrieval, and forgetting of fear memory. These studies suggested that mechanisms for fear memory regulation are shared by humans and other higher animals. Additionally, rodent studies have identified the mechanisms of fear memory at the molecular, cellular, and circuit levels. Findings from these studies in rodents have been applied to facilitate the development and improvement of PTSD intervention. For instance, reconsolidation and extinction of fear memories have been applied for PTSD treatment to improve prolonged exposure (PE) therapy, an effective psychotherapy for PTSD. Combination of medications weakening retrieved traumatic memory  with PE therapy may contribute to improvement of PTSD. Interestingly, a recent study in mice identified forgetting of fear memory as another potential therapeutic target for PTSD. A better understanding of the mechanisms involved in fear memory processes is likely to facilitate the development of better treatments for PTSD. This review describes fear memory processes and their mechanisms and discusses the pros and cons of applying how this knowledge can be applied in the development of interventions for PTSD. Post-traumatic stress disorder (PTSD) is a mental disorder associated with traumatic memory, including fear memory. In experimental animals, Pavlovian fear conditioning has been widely used as a model of PTSD. The most widely used fear conditioning paradigms are based on a contextual or cued fear conditioning task, in which a rodent learns the association  between the conditioned stimulus (CS), such as a chamber (context) or a tone (cue), and an unconditioned stimulus (US) inducing fear, such as mild electrical foot shocks (Phillips and LeDoux When re-exposed to the chamber (context) or the tone (cue), the conditioned rodent shows immobile freezing (fear) responses by retrieving the conditioned fear memory. Generally, fear memory is assessed based on the duration of the freezing response during re-exposure to the CS (chamber or tone) for a certain period of time .2+/calmodulin-dependent protein kinase IV, which regulate the activation of CREB  is stable while short-term memory  is labile. The process of stabilizing a labile STM is known as “memory consolidation”    initially but gradually less so over time. This phenomenon is defined as “memory extinction”  following (within a few hours) retrieval of the memory (reconsolidation-update)  is an antagonist of the NMDA glutamate receptor and is a therapeutic agent for Alzheimer’s disease Bormann . InteresIt is important to note that MEM might block memory retention through inhibition of NMDA receptor activation . Therefore, it is possible that robust traumatic memories remain hippocampus-dependent without being rendered hippocampus-independent since spontaneous and continuous retrievals may continue to induce hippocampus-dependent destabilization/reconsolidation loops (see above). It is also likely that forgetting can be induced without manipulation of traumatic memories such as long-duration memory retrieval described above.The promotion of hippocampal neurogenesis is thought to enhance forgetting of not only traumatic memories selectively but also other hippocampus-dependent memories. This represents a disadvantage with respect to PTSD treatment since even important memories will be forgotten as a result of increased adult hippocampal neurogenesis although there may be protective mechanisms that act to maintain important memories. However, targeting forgetting may still be beneficial for PTSD treatment if patients show severe PTSD symptoms, even though forgetting of any hippocampus-dependent memories would be promoted during the treatment of PTSD. Therefore, the advantages and disadvantages of promoting forgetting processes in the PTSD treatment should be carefully considered. However, as supported by the observation that exercise enhances forgetting (Ishikawa et al. Our findings suggest that targeting forgetting processes can be a potentially viable alternative or adjunct to extinction and reconsolidation-based approaches. Interventions that promote the forgetting of traumatic memory may be useful for improving the efficacy of PTSD treatment.PE therapy is an effective cognitive therapy for PTSD. While interventions to treat PTSD have focused on reconsolidation/destabilization and extinction, it has been suggested that induction of forgetting could shorten and/or improve PE therapy since continuous/repeated traumatic retrieval is not required for the enhancement of forgetting of traumatic memories by neurogenesis enhancers. Thus, interventions that promote forgetting may represent an alternative approach for modifying traumatic memories. To improve PTSD therapy via the targeting of memory processes, it will be necessary to further investigate the mechanisms underlying fear memory regulation at the molecular and cellular levels, so as to identify more efficient targets that can enable the artificial regulation of memory processes. Additionally, the simplest means of identifying novel therapeutic targets for the modification of traumatic memories would be to utilize existing medications, such as MEM, that have been used for the treatment of Alzheimer’s disease. Furthermore, it is also important to develop valid animal models of PTSD as several laboratories have tried to develop PTSD models using rodents (Rau et al.


A strong association exists between stroke and dementia with both diseases linked to ageing. Survival rates from stroke are improving which would equate to an ever-expanding population of patients at risk of future dementia. Early or timelier identification of dementia has become a priority in many countries, including the UK. Although screening for dementia is not advocated, targeting at risk populations could be used to reduce an individual’s risk via intervention , where available. One approach to improving identification of high-risk dementia individuals is using risk prediction models. Such models could be applied to stroke survivors. Dementia risk prediction models specific to stroke survivors have recently been developed and will be discussed here.  One in three people will experience stroke, dementia or both at some stage in their lives ,2. StrokImpaired cognition following stroke has traditionally been associated with vascular disease. Cerebral small vessel disease is thought to be a major contributor to vascular dementia and is often considered to be a distinct entity from Alzheimer’s disease . HoweverNumerous risk factors for cognitive decline and dementia have been identified in stroke survivors. These include well-known risk factors for dementia such as age and a history of cardio-metabolic disease, atrial fibrillation, lower educational attainment as well as stroke specific factors , pre-stroke cognitive impairment and neuroimaging markers including severity of white matter changes, medial temporal lobe atrophy and hippocampal changes  ,16,17. AGiven the association between vascular factors and risk of dementia, several trials have been undertaken to determine whether dementia risk can be reduced in stroke patients focusing on vascular based interventions. The results have been largely disappointing. One study, The Perindopril Protection against Recurrent Stroke study, found that blood pressure lowering in individuals with a history of stroke or transient ischaemic attack did reduce the risk of dementia and cognitive decline but associated with recurrent stroke . In a stRisk prediction in the context of stroke is not novel. Indeed, risk models have been developed for predicting stroke in whole populations  as wellIn contrast to the development and use of scores for predicting risk of stroke and health-related outcomes  post-stroke, to date very few models have been developed for the prediction of cognitive impairment and dementia. Cognitive dysfunction post-stroke is both common and severe particularly as early post–stroke cognition has been associated with long-term functional outcomes . FurtherCriteria for Mild Cognitive Impairment (MCI) describe an intermediate stage between normal cognition and dementia, associated with increased dementia risk, namely Alzheimer’s disease . It is tMoving away from the concepts of MCI/VCI, more recently, similar to the development of risk prediction models for other diseases such as cardiovascular disease (CVD) ,39, acutHowever, it is well established that different disease populations , are at greater risk of dementia compared to normal controls. Being able to identify individuals at high risk of dementia co-morbid with other conditions is important as it could: (1) assist in timely identification; (2) allow for personalised treatment to reduce risk, where available; (3) assist with intervention development; and, (4) assist patients, their families and clinicians with future planning. Given this, new disease-specific dementia prediction models have been developed for people with type II diabetes  and now Although the primary focus has been on prediction of dementia rather than cognitive impairment, current PSD risk prediction models do not distinguish between dementia subtypes, have not been stratified by age or sex and have been developed predominately in Caucasian samples raising questions of generalisability. Further, most models have a relatively short predictive period and it may be useful to look at the risk of cognitive decline and dementia over longer periods particularly in those who have a stroke at a younger age.There has been an increased interest towards timelier identification of those at high risk of dementia so that individuals can access treatment and support earlier. Risk of cognitive impairment and dementia increases after stroke. Therefore, stroke-survivors represent one population where determining future risk of cognitive impairment and dementia could have numerous benefits such as improved access to support, treatment and potentially stricter adherence to secondary vascular prevention to improve prognosis. Further work is required to develop and validate models to predict post-stroke cognitive impairment and dementia and to assess their feasibility, cost-effectiveness and acceptability to patients as well as health care professionals. Although we may develop and validate models in various populations, risk assessment for PSD is not without its challenges. In particular, assessing the acceptability to patients and their families is even more important given the potential psychological effects a “high risk for future dementia” assessment outcome may have. Future studies need to assess how this process could take place in post-stroke clinical care to ensure universal acceptability of such an approach.


In recent years, the field of sexual selection has exploded, with advances in theoretical and empirical research complementing each other in exciting ways. This perspective piece is the product of a “stock-taking” workshop on sexual selection and sexual conflict. Our aim is to identify and deliberate on outstanding questions and to stimulate discussion rather than provide a comprehensive overview of the entire field. These questions are organized into four thematic sections we deem essential to the field. First we focus on the evolution of mate choice and mating systems. Variation in mate quality can generate both competition and choice in the opposite sex, with implications for the evolution of mating systems. Limitations on mate choice may dictate the importance of direct vs. indirect benefits in mating decisions and consequently, mating systems, especially with regard to polyandry. Second, we focus on how sender and receiver mechanisms shape signal design. Mediation of honest signal content likely depends on integration of temporally variable social and physiological costs that are challenging to measure. We view the neuroethology of sensory and cognitive receiver biases as the main key to signal form and the ‘aesthetic sense’ proposed by Darwin. Since a receiver bias is sufficient to both initiate and drive ornament or armament exaggeration, without a genetically correlated or even coevolving receiver, this may be the appropriate ‘null model’ of sexual selection. Thirdly, we focus on the genetic architecture of sexually selected traits. Despite advances in modern molecular techniques, the number and identity of genes underlying performance, display and secondary sexual traits remains largely unknown. In-depth investigations into the genetic basis of sexual dimorphism in the context of long-term field studies will reveal constraints and trajectories of sexually selected trait evolution. Finally, we focus on sexual selection and conflict as drivers of speciation. Population divergence and speciation are often influenced by an interplay between sexual and natural selection. The extent to which sexual selection promotes or counteracts population divergence may vary depending on the genetic architecture of traits as well as the covariance between mating competition and local adaptation. Additionally, post-copulatory processes, such as selection against heterospecific sperm, may influence the importance of sexual selection in speciation. We propose that efforts to resolve these four themes can catalyze conceptual progress in the field of sexual selection, and we offer potential avenues of research to advance this progress. The flowers of an alpine meadow, antelope horns, a dawn chorus of songbirds: all are snapshots of long histories of sexually selected diversification and exaggeration of signals and displays that have or once had effects on mating or fertilization success. For sexually reproducing organisms, intrasexual competition for reproductive opportunities is a powerful selective pressure, not only shaping the extravagant ‘secondary sexual characters’ that Darwin originally set out to explain, but also with obvious potential to reinforce or even trigger speciation and dramatically affect macroevolution and biogeography. To explore biodiversity without an understanding of sexual selection is a bit like laying a jigsaw puzzle upside down. With our current insight that reproduction is the hard currency of natural selection, it may seem strange that the notion of sexual selection required such a massive volume of reasoning and countless examples . In procellariform birds, high olfactory bulb-to-brain ratios co-occur with long-term genetic monogamy  may be subject to mate selection. Given a genetic basis of a trait it can also respond to selection. Importantly, this means that many traits that are traditionally seen as products of natural selection are likely to also be affected by sexual selection, and hence pushed away from their naturally selected optima. That parental care can be under sexual selection is already well established , but a bThe level of polyandry of a population will likely reflect the outcome of interactions between male- and female-driven strategies. Whereas male strategies are often assumed to drive and females to resist polyandry, some degree of polyandry can be adaptive and actively promoted by females. Importantly, polyandry is likely to have drastic effects on the operation of sexual selection on males. The key implication is that polyandry creates a new source of variation in male reproductive success in the form of variation in paternity share arising from multiple matings by females and male-male competition over access to fertilization.The resulting two episodes of postcopulatory sexual selection  add considerable complexity to the architecture of variation in male fertilization success , and conper se, a supposition supported by male–female relatedness interactions on a male’s probability of paternity (vs. scramble) also affects expenditure on pre- and post-mating male adaptations  mating success and (postcopulatory) paternity share, such trade-offs may play a considerable role in the evolution and maintenance of alternative mating tactics . As moreFinally, while polyandry was originally assumed to exacerbate sexual conflict, there is increasing appreciation that polyandry may have a more nuanced effect, by relaxing conflict over some precopulatory decisions  or alleles that make a good match to her own alleles (compatible genes). What constitutes a favourable allelic match should be investigated by analyzing the fitness of individuals with different allelic repertoires . If maxiA further challenge will be to reveal a possible mechanism for the mating preference; either there could be pre-copulatory cues for a behavioral discrimination among males, or cryptic female sperm selection mechanisms in the oviduct or at the ovum . A recenInbreeding affects fitness negatively in a wide range of taxa , with anInbreeding avoidance: when markers matter’). Recent software developments, such as Rhh . Therefore, two selective forces may underlie MHC-based mate discrimination, inbreeding avoidance and enhanced immunocompetence. The function of MHC in mate choice and the importance of disentangling these two fitness-related phenomena has been demonstrated in wild Atlantic salmon  (Lacerta agilis)  , and in  agilis) . SpecifiAlthough MHC loci may still act as a cue for kinship in some systems , and efficacy . In the sections below, we discuss developments and challenges in these two areas.The proximate physiological and neurological mechanisms for production, emission and perception of signals are essential keys to both adaptive and non-adaptive aspects of sexual communication. In particular, the design and evolutionary trajectories of signals are shaped by both First, the mediation of signal honesty in many study systems likely depends on a dynamic and complex integration of social and physiological costs, which may be both spatially and temporally variable. It can be a formidable empirical challenge to measure the “right” parameters at the right time, but for detailed understanding of honest signaling, this is the way forward.Second, and especially relevant to the biodiversity theme of our workshop, we address the increasingly appreciated impact of receiver biases  on both design and diversification of sexually selected traits  The pleiotropic actions  of key bThe degree to which social enforcement vs. physiological costs mediate signal honesty likely varies with social context  and it is clear that social costs can have physiological outcomes and vice versa. For example, testosterone stimulates aggressive behavior, and social aggression itself can increase testosterone further . In contrast to such ‘sender-precursor models’  signaling systems presents a very different context. Firstly, agonistic signals have the potential to be emancipated from the constraints of direct linkage to male quality; some mechanism must maintain signal honesty, which may be achieved through socially mediated costs. Thus, agonistic signals may be more evolutionarily labile than epigamic signals, potentially allowing for higher rates of change in signal form. Secondly, the time scale for signal information to manifest can be much shorter for agonistic signals; a male can test the honesty of another male’s signal directly. This interaction also sets the stage for a learning-based receiver bias, essentially a discrimination task analogous to those shown to generate ‘generalization’ in the psychology literature ; Table 1Euplectes spp), displaying varying degrees of signal exaggeration  undergo a type of cycling characterized by rapid evolution  illustrate the latter point , and more such are required to make general conclusions. For this to be possible, long term studies with careful observations and detailed knowledge of natural history combined with genomic data is the only remedy.Importantly, genotype effects on mating success may be context dependent, as appears to be the case in great snipes. The effect of candidate SNPs (Single Nucleotide Polymorphism) on great snipe mating success depended on whether birds were infected with avian malaria, as revealed by significant interaction terms among infection status and genotype in a few loci . GenomicA classic question in sexual selection theory is to what extent the evolution of secondary sexual traits is constrained by the exhaustion of genetic variation resulting from the process of selection itself  could also be rejected  germline negatively affected courtship displays but not colouration, indicating that the former is a large mutational target . Moreover, How does sexual conflict impact speciation processes?’ below, we discuss how genomic approaches can be used to test the prerequisites for sexual and natural selection to jointly promote speciation.There are several possible solutions to this “problem”. First, female mate preferences may actually experience corresponding natural selection pressures as male display traits. Choice mechanisms directly based on conspecific sperm traits rather than species-specific secondary sexual traits are known from external fertilizers, like abalones, sea urchins and oysters  and fishAlthough pre-copulatory mate choice based on plumage and song traits is well known in passerine birds, little attention has been paid to possible post-copulatory reproductive barriers. Passerine sperm morphology is known to evolve rapidly e.g.,  and the Ficedula flycatchers, suggests that female pied flycatchers (F. hypoleuca) that are constrained to pair with heterospecific males, are more prone to perform extra-pair copulations with conspecific males and able to exert cryptic choice in favour of their sperm, thereby reducing the risk of producing unfit hybrid offspring  males experienced a higher velocity reduction in pied flycatcher female fluid than in collared flycatcher fluid, but not vice versa. Furthermore, this effect was strongest for pied flycatcher females with a high likelihood of previous exposure to sperm of collared flycatcher males. Such effects were not seen in studies of four other, non-hybridizing passerine species pairs, with a range of divergences in genetic distance and sperm morphology  is often directly associated with dominance strategies and thereby access to other resources than females . We therIn contrast to sexual selection, less research has targeted the consequences of sexual conflict on speciation. Several approaches concur with the notion that sexual conflict will also catalyse speciation, others suggest the reverse  in mammals, butterflies and spiders were unsuccessful  male A ×female B matings may differ from that in (ii) female A x male B matings. Additionally, the balance for the sexes between the fitness value of winning  and ‘power’ (the fitness cost of overcoming defences) may differ in these two possible pairings . Such asGenetic architecture of sexual selection’ above) and then be placed into the context of speciation. Because, as mentioned above, divergent sexual selection alone rarely causes speciation (Heliconius butterflies, where the mimicry pattern also has a signaling function when acquiring mates (Pundamilia cichlid fish and Heliconius butterflies, where gene flow is evident and multiple effect traits have been invoked to be instrumental in the speciation process, empirical results are consistent with few genes having a major effect on female assortative mating (Genomic approaches may help to bridge several important gaps in our current understanding of the role of sexual selection in speciation. Detailed information about the genomics underlying sexually selected phenotypes can be used to test key assumptions of theoretical models on sexual selection (eciation , one pareciation ; Table 1eciation . The comeciation . The comeciation . One of ng mates . Howevere mating .per se does not impose a key function in the speciation process. To achieve this goal several different methods need to be combined. First, ecological and behavioral studied are needed to reveal the function of phenotypic traits and their role in niche use, mating and most importantly their barrier effects - their role in causing reproductive isolation. Second, the genetic variants underlying these traits need to be revealed with genome wide association studies or similar (GWAS, When several different traits contribute to reproductive isolation, linkage disequilibrium among the underlying loci may shelter against the homogenizing effects of gene flow. ar GWAS, . FinallyOur survey of emerging questions in sexual selection, while necessarily incomplete, shows that the field is on the cusp of a major revolution. In many ways the theoretical framework for the study of sexual selection and sexual conflict is robust, having been refined since the late 1960s. What is needed now are bold empirical attempts to understand the diverse molecular and ecological mechanisms that could modulate the outcomes of sexual selection and sexual conflict.One obvious frontier of sexual selection resides in increased understanding of the molecular genetic and physiological mechanisms of traits subjected to or contributing to sexual selection and sexual conflict, an understanding that next-generation molecular methods will help achieve. Although interesting in its own right, it is perhaps even more important what these mechanisms imply about the history, constraints and evolvability of traits, allowing several outstanding issues in sexual selection and sexual conflict to be addressed. A molecular understanding of sexually selected traits will help the field discriminate between alternative hypotheses for the maintenance of variability in those traits, for example, whether they have evolved via good genes mechanisms or by more arbitrary or neutral processes . A good It would, however, be short-sighted to conclude that molecular mechanisms alone will bring a holistic understanding of sexual selection and conflict. Genetic mechanisms only have meaning when appropriately placed in the context of the natural history and ecological and social constraints that characterize different systems exhibiting sexual selection. Recent examples show how molecular methods achieve their biggest impact when deployed in the context of large-scale ecological and behavioral studies of naturally occurring variation in the wild e.g., . And altAdvances at the interface of molecular, ecological, behavioral and theoretical research will require collaborations between experts in divergent areas, a goal that we hope our workshop in Gothenburg has fostered.


Studies based on high-quality linked data in developed countries show that even minor linkage errors, which occur when records of two different individuals are erroneously linked or when records belonging to the same individual are not linked, can impact bias and precision of subsequent analyses. We evaluated the impact of linkage quality on inferences drawn from analyses using data with substantial linkage errors in rural Tanzania.Semi-automatic point-of-contact interactive record linkage was used to establish gold standard links between community-based HIV surveillance data and medical records at clinics serving the surveillance population. Automated probabilistic record linkage was used to create analytic datasets at minimum, low, medium, and high match score thresholds. Cox proportional hazards regression models were used to compare HIV care registration rates by testing modality (sero-survey vs. clinic) in each analytic dataset. We assessed linkage quality using three approaches: quantifying linkage errors, comparing characteristics between linked and unlinked data, and evaluating bias and precision of regression estimates.n = 263) and clinics (n = 142). Automated probabilistic linkage correctly identified 233 individuals  at the low threshold and 95 individuals (PPV = 90%) at the high threshold. Significant differences were found between linked and unlinked records in primary exposure and outcome variables and for adjusting covariates at every threshold. As expected, differences attenuated with increasing threshold. Testing modality was significantly associated with time to registration in the gold standard data . Increasing false matches weakened the association . Increasing missed matches  was strongly correlated with a reduction in the precision of coefficient estimate .Between 2014 and 2017, 405 individuals with gold standard links were newly diagnosed with HIV in sero-surveys (Similar to studies with more negligible levels of linkage errors, false matches in this setting reduced the magnitude of the association; missed matches reduced precision. Adjusting for these biases could provide more robust results using data with considerable linkage errors. A growing number of demographic and epidemiological research studies are conducted using linked datasets from multiple sources . In the A recent Wellcome Trust report detailed how record linkage adds to the value of medical research in low- and middle-income countries . A uniquThe linked data infrastructure created by PIRL includes gold standard links between HIV serological survey data and manually digitised medical records from three clinics serving the surveillance population, two of which offer HIV testing services while the third enrols HIV-positive individuals into care. As an illustrative example to evaluate linkage errors, we tested whether individuals who receive their first HIV diagnosis during a village-based HIV serological survey enrol for HIV care services quicker than those who receive their first HIV diagnosis in a clinic that also offers HIV testing. For this analysis, we first assessed the relationship between diagnosis location and time to enrolment into HIV care in the gold standard linked data. We then conducted automated record linkage, a process that included no human interaction or involvement like PIRL, to create four test datasets based on varying levels of match score threshold. Linkage errors, including false and missed matches, were quantified in each test dataset, overall and by individual characteristics. Finally, we determined whether and how linkage errors impacted the analysis of the primary research question by comparing the characteristics of linked and unlinked records and the bias and precision of regression coefficients.The Kisesa observational HIV cohort study was established in 1994 and is located in a rural ward in the Magu district of Mwanza region in northwest Tanzania ) of individuals diagnosed in a clinic subsequently registered for HIV care by the study cut-off date, compared to 42 (16%) of those diagnosed in the sero-survey (p < 0.0001).During the study period, 263 and 142 individuals with gold standard links received their first positive HIV diagnosis in the sero-survey and clinics, respectively  Table . A majorOf the 405 gold standard links, automated linkage correctly identified 248 records, falsely matched 157 records, and missed 157 records at the minimum match score threshold. This resulted in a sensitivity and positive predictive value (PPV) of 61% and a false match rate of 39% .There was a significant association between testing modality and time to registration at the CTC in the linked gold standard data in favour of those receiving their diagnosis at a walk-in clinic   introduced bias at all match score thresholds. False matches reduced the magnitude of the association between the tested exposure and outcome while increasing numbers of missed matches reduced the precision of these estimates, which is comparable to analyses in settings with higher quality data , 11, 29.We used standardised differences to identify variables that were more affected by linkage error and potential sources of bias as was done in previous studies . We founWe found measurable bias in the regression coefficient of the primary exposure at every match score threshold. Selection bias is likely to have impacted the analyses given that selection into the linked datasets was related to both the exposure and outcome , 33. TheOur findings suggested the optimal point that balanced trade-offs between false and missed matches  was at the minimum match score threshold. However, optimisation in this context is inappropriate because there were large biases in the primary regression coefficient at this and all other match score thresholds, which would have led to misleading interpretations of the results. While the consequence of optimisation in our primary analysis would have resulted in a biased measure of the association between variables found in different data sources, a potentially more appropriate use of optimisation may have been to obtain a count outcome from a single data source. The proportion of individuals who registered at the CTC (outcome) was 29% in the gold standard data and ranged between 17 and 19% in the automated linked datasets. Therefore, if our research question was to obtain the proportion or rate of individuals who registered at the CTC our conclusions would also have been meaningfully different at every match score threshold. While optimisation was possible with our data, we conclude there was no optimal threshold that balanced trade-offs between PPV and sensitivity as well as resulted in unbiased associations between two variables or count outcomes of a single variable.A strength of this analysis was the access to individual-level data collected in the PIRL software, clinics, and sero-surveys. This information is often only available to individuals performing the linkage and not to researchers conducting analyses –39 and aThere were some limitations. First, the magnitude of the tested association between the selected exposure and outcome was large in the gold standard data, which was probably why the conclusions of the primary regression analysis were similar in the automated linked datasets at the lower match score thresholds even after measurable attenuation in the estimate. It is likely that a more modest association found in the gold standard data would have resulted in a null association and therefore different conclusions as has been found in other studies . Second,Recently, there has been increased attention on how errors arising during the linkage process impacts inferences drawn from analyses using imperfectly matched data, but predominately in high-income countries with negligible linkage errors. We provided original evidence that the impact of linkage quality is similar in a low-income country setting with substantial linkage errors. We plan to investigate methods that minimise or correct for these biases and provide more robust results using data with considerable linkage errors. Until these analyses are complete, our results suggest that researchers in similar settings desiring to perform probabilistic record linkage should allocate resources toward PIRL or similar system[s].


Aspirin remains among the most widely used medications across the globe, not only for secondary prevention but also for primary prevention of cardiovascular disease (CVD), with nearly 36 million adults without prior CVD event taking aspirin in the US alone . Since iIn 2018, 3 pivotal trials raised questions regarding benefits of aspirin in primary prevention, leading to a new update in the preventive care guidelines from the AHA/ACC .The major advancements in healthcare have led to a dramatic increase in life expectancy over the past century with a substantial demographic shift toward aging of population. It has been shown that the risk of CVD doubles with each decade of life independent of traditional risk factors . This haAspirin use for secondary prevention in all populations has been widely accepted, as the benefits linked to reduction in myocardial infarction and stroke are likely to overweigh the risk of major bleeding. However, as shown in our meta-analysis the risk-benefit has not been favorable in primary prevention trials. Of note, while no major trial exclusively enrolled elderly population, except for the Effect of Aspirin on Cardiovascular Events and Bleeding in the Healthy Elderly (ASPREE) trial , subgrouIn ASPREE trial conducted exclusively in healthy adults ≥70 years of age (or ≥65 years of age among blacks and Hispanics), low-dose aspirin not only failed to lower the risk of CVD, it significantly increased the risk of major bleeding events. Aspirin also failed to show any benefit in terms of disability-free survival [There is a greater bleeding risk with increasing age, with about 50% increase in the risk of hemorrhagic stroke and nearly double the risk of major extracranial bleeding with each decade of age regardless of aspirin use. Therefore, it is important to quantify the relative risk reduction of CVD events and balance it with higher bleeding risk. Elderly patients also tend to have multiple comorbidities, as well as chronic pain leading to relatively higher consumption of over-the-counter non-steroidal anti-inflammatory drugs (NSAIDs) that can increase the risk of gastrointestinal (GI) bleeding either through mucosal irritation or potentiation of aspirin’s antiplatelet effect.Another area of debate with aspirin is the proposed benefit in reducing cancer especially colorectal cancer. While prior studies suggested possible reduction in cancer incidence and cancer-related deaths, recently studies failed to confirm this phenomenon ,7,8. ImpThe current guidelines recommend against the use of aspirin for primary prevention in adults >70 years of age as the risk of major bleeding is likely to overweigh the potential benefit in reducing CV events, and the less likelihood to observe the expected benefit of reducing cancer risk . With thVarious other questions regarding aspirin use still exist. Should individuals who are taking aspirin and have reached 70 years of age without any adverse effects continue aspirin therapy? Obviously, they should discuss with their clinician, and decision be based on their overall CVD risk and personal preferences. Also, should aspirin use be continued for secondary prevention in patients who have done well for years after their CV event as “life-long therapy”, especially in subjects ≥70 years of age? We certainly do not have answers for this question. Perhaps future studies will address this important question.In summary, the use of aspirin for primary prevention of CVD and cancer is debatable, especially in the elderly population. Health education is recommended to reduce the risk of complications associated with “over-the-counter” use of aspirin for primary prevention.


Investigating the bases of inter-individual differences in risk-taking is necessary to refine our cognitive and neural models of decision-making and to ultimately counter risky behaviors in real-life policy settings. However, recent evidence suggests that behavioral tasks fare poorly compared to standard questionnaires to measure individual differences in risk-taking. Crucially, using model-based measures of risk taking does not seem to improve reliability. Here, we put forward two possible – not mutually exclusive – explanations for these results and suggest future avenues of research to improve the assessment of inter-individual differences in risk-taking by combining repeated online testing and mechanistic computational models. In a recent series of studies Low external validity and-reliability is extremely worrying for the development of behavioral economics applications and (by extension) for the neuroeconomics research framework, where risk preferences are commonly assessed and elicited using behavioral tasks. In addition, the unreliability of behavioral measures is also problematic for the computational psychiatry research framework that has recently placed great emphasis on the use of cognitive and behavioral phenotyping tools. The idea behind these frameworks is that behavioral measures can be used to phenotype patients at the individual level and ultimately work as tools to perfect diagnosis, personalize care, and assess the efficacy of new treatments or drugs in clinical trials . In thisquestionnaires – explain real life behaviors better than behavioral measures – that are based on choices? And why would the same subjects produce different choices when presented with the very same task twice?In addition to questioning approaches based on behavioral phenotyping tools, these findings also raise a profound epistemological challenge. Given that real life frequency of risky behaviors is the reflection of past choices, why then, do personality measures – that are based on problem with the instrument; The other possibility is that these findings reflect a problem with the construct.We put forward two possible answers for these puzzling results and fundamental questions : The first possibility is that these findings reflect a problem with the instrument” argument has been explicitly put forward by the authors of the studies . In statistical terms, this would result in an artificially increased correlation between frequency and personality measures. Taken together, these features may inflate the consistency and validity of the personality measures. Finally, self-reported questionnaires are well-known for eliciting edulcorated representations that are influenced by a range of social norms .Propensity measures on the other hand, are designed to maximize inter-individual differences. In addition, a good test-retest reliability is a al norms . To overThe argument that there is a “problem with the instrument” also applies to the mathematical model used to quantify risk propensity parameters. The authors indeed focused on CPT, which is a widely used descriptive model originally designed to explain one-shot decisions. But three features of CPT may undermine the internal consistency of model-based measures of risk sensitivity . First, problem with the construct” argument implies that behavioral tasks provide a genuine estimate of the subject’s momentary risk attitude at the time of testing, but that risk attitude itself changes over time. This is plausible if we assume that momentary risk attitude is influenced by multiple factors. To illustrate this idea, we now consider a simplified case involving two possible phenotypes, a risk-seeking phenotype (red) and a risk-averse phenotype (blue), and we propose a multi-layer model in which momentary risk attitude corresponds to the weighted sum of different sources of influence that change with different time constants  and reliability (between-tasks consistency and test-retest reliability). We delineate two possible – not mutually exclusive – interpretations of these results. The pessimistic “problem with the instrument” argument states that behavioral tasks are not suited to investigate inter-individual differences. The optimistic “problem with the construct” argument states that variability in behavioral tasks reflects true changes in momentary risk attitude. According to this view, behavioral tasks reflect true momentary risk attitude and will the quantification of the relative weights of the different layers.At the moment, personality questionnaires appear to be the best psychological tools to predict the frequency of real-life risky behavior. Should we then, abandon the quest for behavioral measures of individual variability? Probably not. Questionnaires are hugely informative when it comes to providing an accurate description of the variability with which personality traits manifest but they cannot be used to trace back the cognitive and neural mechanisms that together produce such variability. The paucity of robust behavioral tools to characterize inter-individual differences therefore constitutes an important obstacle in building proper models of cognitive variability.active and adaptive ones. Adjusting task parameters online could indeed correct for momentary changes in baseline performance that may affect the assessment of risk preferences. These results also highlight the importance of repeated testing, which has now become considerably easier with the development of smart-phone based behavioral experiments. Repeated testing should also allow us to test the multi-layer hypothesis, to attribute precise coefficients to the different layers, and by averaging performance over experiments, to infer participants’ trait-level phenotype. The issue related to the ambiguous relationship between CTP parameters and behavioral profiles and their correlation may be solved by implementing principal component analyses instead of working with the raw parameters and by implementing hierarchical model fitting (mechanistic and dynamic models of risk preferences that integrate learning processes and contextual factors, might also allow for a better quantification of risk preferences at the individual level. A promising way to design these models could be the development of choice prediction competitions, a method that already commonly used in the machine learning literature (Developing behavioral biomarkers, however, requires a proper re-think in the way cognitive scientists design tasks so that they maximize between-subjects variance. One promising possibility is to shift from fixed and passive designs to  fitting . This apterature . Even moSP designed the review. SP and CC wrote the review.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.