The modern healthcare system is directly related to the development of digital health tools and solutions. Pills with digital sensors represent a highly innovative class of new pharmaceuticals. The aim of this work was to analyze the patent landscape and to systematize the main trends in patent protection of digital pills with ingestible sensors worldwide; accordingly, to identify the patenting leaders as well as the main prevailing areas of therapy for patent protection, and the future perspectives in the field. In July 2022, a search was conducted using Internet databases, such as the EPO, USPTO, FDA and the Lens database. The patent landscape analysis shows an increase in the number of patents related to digital pills with ingestible sensors for mobile clinical monitoring, smart drug delivery, and endoscopy diagnostics. The leaders in the number of patents issued are the United States, the European Patent Office, Canada, Australia, and China. The following main areas of patenting digital pills with ingestible sensors were identified: treatment in the field of mental health; HIV/AIDS; pain control; cardiovascular diseases; diabetes; gastroenterology (including hepatitis C); oncology; tuberculosis; and transplantology. The development of scientific and practical approaches towards the implementation of effective and safe digital pills will improve treatment outcomes, increase compliance, reduce hospital stays, provide mobile clinical monitoring, have a positive impact on treatment costs and will contribute to increased patient safety. Nowadays, in the modern world the progress of the healthcare system is directly related to the development of digital health tools.According to the WHO global strategy, digital technologies are connected to the future of world health. Digitalization has the potential to benefit health promotion, maintain global security, and provide services to the most vulnerable groups of the population .Digital pills occupy an important place among the digital health solutions. Digital pills contain integrated sensors that allow monitoring of the course of pharmacotherapy through an interaction with the software of, e.g., tablets and smartphones. Such monitoring is of great importance, as low patient compliance (medication opt-out) is a major challenge for all areas of medicine.Digital pills improve treatment adherence and efficiency in the field of mental health and behavioral modifications, such as schizophrenia, bipolar I disorder, attention deficit and hyperactivity disorder, drug abuse, smoking, pain, insomnia, and many others. The developers of the digital pills also focus on the treatment of cardiac disorders, diabetes, hepatitis C, AIDS, cancer, tuberculosis, and the monitoring of patients’ use of opioid drugs after surgery, and other conditions when admission may be impaired due to the characteristics of the patient’s behavior  ,3,4.Digital pills have a significant potential for savings in healthcare costs by reducing the need for emergency medical care and the hospitalization of patients. The annual costs of non-compliance range from USD100 billion up to USD290 billion in the US, EUR1.25 billion in Europe, and approximately USD7 billion in Australia. In addition, 10% of the hospitalizations among the elderly are due to treatment noncompliance, with a typical noncompliant patient requiring three additional doctor visits per year, resulting in an annual increase of USD2000 in treatment costs. In diabetes, the estimated cost savings associated with improving noncompliance ranges from USD661 million to USD1.16 billion. Non-adherence is thus a critical clinical and economic problem [Despite the progress made in this area to date, there are still a number of barriers to the widespread implementation of digital pills into medical practice. They include issues of clinical efficacy, safety, treatment costs, and confidentiality, among others. In addition, the patent landscape for the digital pill with ingestible sensors is not yet well-established. This indicates the need for further research in this area ,7.The development of digital pills is executed by high-tech industries that are evolving rapidly and require innovation from manufacturers. One of the sources of information reflecting the innovation process is the patent documentation.The value of information, which is formed as a result of the work of patent offices in different countries around the world, is its universality in determining the main technological trends and building trends in market processes, and in analyzing the behavior of specific market participants, their resources, and growth prospects. The universality of patent data is ensured by the unification of standards for the presentation of data on intellectual property objects. The reliability of patent information is ensured by the procedure of the state registration of intellectual property rights. The scope of their legal protection depends on the completeness of the disclosure of information about the objects, as well as on the concretization of the features that constitute the novelty of the results of intellectual property. Therefore, in order to ensure a comprehensive protection of their own exclusive rights, the applicant is forced to detail the important technological aspects of patented development as much as possible. The examination of the patent landscape enables researchers to quantify the intellectual property characteristics.The aim of this work was to analyze the patent landscape and systematize the main trends in the patent protection of digital pills with ingestible sensors worldwide, as well as to identify the patenting leaders, the main prevailing areas of therapy for patent protection, and future perspectives in the field.By the end of June 2021, there were 137 digital therapeutic products and 122 digital care products at different stages of development, according to the IQVIA Digital Solutions database, which systematizes the different types of digital healthcare solutions . Among tAn analysis and systematization of the global patent protection of digital pills with ingestible sensors was completed, to identify the key developments in the sector .A stable increase in the dynamics of applications and granted patents during the period of time between 2010 and 2018 was revealed. Most of the applications (49) were filed in 2017, and most of the patents (15) were granted in 2018. The lower patent activity in the years 2019–2022  may be associated with a focus on commercialization and the entry into the market of newly created inventions instead of the filing of new patents.The patenting landscape presents a strong indication of the continuous efforts of scientists in the development of digital pill forms. It should be noted that some of the patents are no longer valid . Given tThe leaders in the number of patents issued are the United States, the European Patent Office, Canada, Australia, and China, which together account for 72% of the total number of patents around the world.The top 20 inventors involved in the creation of digital pills with ingestible sensors are shown in The analysis  revealedAbilify MyCite is an atypical antipsychotic equipped with an ingestible sensor for the treatment of adults with schizophrenia, the acute treatment of adults with manic and mixed episodes associated with bipolar I disorder, and for use as an adjunctive treatment for depression in adults. A serious problem associated with psychotropic drug treatment is adherence to the treatment plan. The side effects of antipsychotics are often debilitating, including weight gain, sexual dysfunction, nausea, and vomiting, and may cause people to change their own doses or stop taking the medication.Aripiprazole, the primary chemical component of Abilify, was discovered by Otsuka Pharmaceutical in 1988, received FDA approval as an antipsychotic in 2002, and has been accessible as a generic drug since 2015.The Abilify My-Cite (aripiprazole tablets with sensor), a drug–device combination product of aripiprazole tablets for oral administration integrated with an Ingestible Event Marker sensor, received the FDA’s first approval of a digital medicine system in 2017.The four major components of Abilify MyCite interact using Bluetooth technology: the medication, which contains the active ingredient aripiprazole; a sensor that transmits a signal to a patch worn on the “lower edge of the rib cage”; a smartphone app; and an online portal. The 1-mm-sized sensor is built into the tablet. It is made of cuprous chloride (copper), magnesium, and silicon and releases a signal to the patch when it encounters stomach acid. When it comes in contact with the stomach acid, the magnesium and cuprous chloride within the sensor react to activate and power the device, and communicate a signal to the patch that is tracking ingestion. This information is then transmitted to the smartphone app .The developed digital pills, such as Abilify MyCite, allow for the clinical monitoring of the treatment of patients with depression.In order to improve the scientific and practical approaches to the management of scientific research in the process of digital pills with an ingestible sensor, an analysis was carried out of Proteus Digital Health and Otsuka Pharmaceutical’s patent strategy for the digital pill, Abilify MyCite .The performed analysis revealed that Abilify MyCite is protected by 32 US patents. This digital pill with an ingestible sensor has six hundred and seventy-one patent family members in forty-one countries.As a result of the patent research, the patenting of a pharmacologically active ingredient aripiprazole and the technologies for its production, methods of treatment, as well as pharma-informatics systems and ingestible event marker systems, was established.The collected data of the present review indicate the prospects and demand for digital pills with ingestible sensors in the global pharmaceutical market.Abilify MyCite is under patent protection until 2030–2033. Licensing, which provides information about the process, is one of the ways to scale and accelerate the global long-term production of this digital drug. It is extremely important that the patent holders have the ability to control the effectiveness and quality of digital pills with ingestible sensors.Proteus Digital Health is a company creating innovative digital health products and once had a huge valuation of USD1.5 billion. However, the company was unable to complete a USD100 million investment round in 2019. In the bankruptcy proceedings in 2020, a US affiliate of Otsuka purchased the technological assets of Proteus for USD15 million .On the one hand, the rational management of intellectual human capital is extremely important in the development of digital pills. It is noted that the development of the digital pills with ingestible sensors, the Abilify MyCite technology, was expensive, and it was necessary to retain the best specialists. On the other hand, an assessment of medical technology is also very important. The average monthly cost of a generic version of Abilify is USD500 to USD800, according to GoodRx. The original digital pills with ingestible sensors, such as Abilify MyCite, cost more than USD1600.In order to reduce the unpredictable rising costs of digital pills, it is imperative to perform comparative studies of the clinical effectiveness when discussing new treatment approaches, and to identify clear advantages over the medicines that are already used in clinical practice.According to the ClinicalTrials.gov website, several clinical trials have been completed using the technology of digital pills with ingestible sensors. A number of digital pill clinical trials are ongoing.The analysis of the patent landscape made it possible to identify the main therapeutic areas in which digital pills with ingestible sensors have proved themselves to be applicable. The following sections summarize the patented digital pills with ingestible sensors in the treatment of various pathological conditions.Diseases of the nervous system.Adherence is especially difficult in patients with serious mental illnesses, such as schizophrenia, schizophrenia-like disorders, and bipolar I disorder, with estimates of nonadherence as high as 50%. Adequate medication is essential to reduce the risk of major adverse outcomes in this population, such as psychosis, symptom recurrence, poor social functioning, hospitalizations, and suicide attempts .As already mentioned above, a striking example of an active innovative strategy for creating digital pills with ingestible sensors is the tactics of Proteus Digital Health, Inc. . The inventions by this company are widely used in neurology and psychiatry. The company was formerly known as Proteus Biomedical, Inc. and changed its name to Proteus Digital Health, Inc. in July 2012.The system, with a conductive element, an electronic component, and a partial power supply in the form of different materials, is described in patent US7978064 by Proteus Biomedical, Inc. The system is turned on when it comes into contact with a conducting liquid, since this completes the power supply and creates a voltage potential. To create a distinctive current signature, the electrical component regulates the conductance between the different materials. The system can be employed in a wide range of applications, such as ingestible event markers, ingestible identifiers, and pharmaceutical compositions with pharma-informatics capabilities.The applicants of patent US8114021 Proteus Biomedical, Inc. disclosed a body-associated receiver, which may be external or implantable. Furthermore, the systems and procedures for using a receiver to coordinate with the dosage distribution systems are described.The inventors of patent US8258962  reported multi-mode communication ingestible event markers and systems, and the methods of using the same. The ingestible event marker consists of an integrated circuit component and upper and lower electrodes and is configured so that when it comes into contact with the stomach fluid, the current flows through the integrated circuit and causes one or more functional blocks in the circuit to emit a detectable signal. The upper and lower electrodes are made of different materials.The pharma-informatics system is demonstrated in patent US8674825 . The automatic detection and identification of the pharmacological compounds actually delivered into the body is a significant new therapeutic tool provided to the clinicians by the present invention. This novel information system and device have numerous applications. Medication delivery, batch, and dose correlation to a physiological response can be achieved when employed in conjunction with other medical sensing equipment. In this way, the clinician may then create the best pharmacotherapeutic regimens. In the cases of accidental and other overdoses, the healthcare professional will be able to establish how far the intake has progressed and how many tablets are involved.The development of a better pharma-informatics system  with a highly regulated identifier activation, where the signal produced by the identifier would be independent of the specific environment, such as stomach contents, the target site where activation is sought, represents another area of interest.n = 28) with bipolar disorder or schizophrenia [n = 44) with schizophrenia, schizoaffective disorder, or first episode psychosis [n = 30) [The effectiveness and safety of the above inventions of Proteus Digital Health were studied in clinical trials: NCT01804257 in patients  .The clinical trials of Proteus Digital Health’s digital pills with ingestible sensors confirmed their high therapeutic efficacy, favorable safety profile, and ability to significantly improve patients’ quality of life. However, further post-marketing clinical trials are needed, including more patients with a high level of evidence.HIV/AIDS.HIV is one of the major global public health problems. Increasing access to effective HIV prevention and treatment allows patients to improve their health .Proteus Digital Health inventions are widely used to monitor adherence in HIV-infected patients.n = 130), 18 years or older with sub-optimal adherence [The digital health feedback system of Proteus  was investigated in the NCT02797262 clinical trial for monitoring and increasing adherence to antiretroviral therapy in HIV-infected patients (n = 100) [n = 30) living with HIV to support ARV adherence [n = 100) taking their oral antiretroviral of TDF/FTC (Truvada) for HIV prevention [Moreover, the Proteus digital health feedback system is planned to be evaluated in the following clinical trials: in NCT02891720 to confirm ingestion of oral FTC/TDF as pre-exposure prophylaxis and to monitor adherence in HIV-negative YMSM (n = 100) ; in NCT0dherence ; and in evention .TM System), the technology of which is disclosed in the patent US9743880 B1 [n = 212) living with HIV (PLWH) who are taking tenofovir alafenamide [The company etectRx  created an ingestible event marker  with Emtricitabine/Tenofovir (TDF/FTC) was investigated in an NCT03842436 clinical trial among MSM (n = 15) with substance use, to monitor PrEP adherence [The ID-Capdherence .Since patient adherence to a medication therapy protocol is essential to preventor avoid costly consequences for the patient or the community, compliance monitoring using digital pills also offers important benefits in the prevention and treatment of HIV.Pain control.Another medical area with a wide use of digital pills with ingestible sensors is pain relief for various pathological conditions. Pain is a cause of passivity and depression. The somatic consequences of both acute and chronic pain are numerous, and sometimes catastrophic. Fever, while also being a protective, biologically appropriate reaction of the body, can at the same time cause a number of negative consequences .The digital pills allow doctors to confirm that a patient actually took the painkillers within the predetermined time frame that they were scheduled to be delivered to them. This is a crucial tool for preventing the unintentional sale of medications that have not yet been consumed.Tremeau Pharmaceuticals, Inc.  specializes in offering non-opioid pain relievers to well-defined patient populations with high unmet needs. The company has created digital pain management pills to treat pain more effectively and with fewer adverse effects.The patent application US2021244672 A1 by Tremeau Pharmaceuticals Inc.  relates to digital pills in the discussed context . An ingeOpioid analgesics are a critical treatment for those patients with advanced-stage pain from cancer. Cancer patients must have pain control as a mandatory and integral element of their treatment. Along with this, there are risks of long-term side effects, including possible abuse and addiction, which is a concern with the long-term use of opioid analgesics in patients who have had cancer.n = 2) with metastatic disease who were experiencing uncontrollable pain. Due to COVID-19′s restriction on site enrollment and the extremely high difficulty in acquiring sites to participate in the study, only two participants were acquired. When the provider of the DMP and the related software filed for bankruptcy and was acquired by a business that had no interest in completing the trial, the study was terminated. Due to a lack of patient data, the investigators did not examine any of the objectives besides the telemedicine feasibility [The Proteus FDA-approved ingestible sensor  was examined in the NCT04194528 clinical study on cancer patients  is a company that developed an ingestible system to detect and reverse opioid overdose. Celero Systems, inventors of CA3149412 A1, disclosed an opioid overdose rescue device that includes an ingestible capsule . A non-rAs a result, there are numerous significant therapeutic uses for the capacity to record with digital pills the consumption of a medicine or other actual exposure of the body to a medicine, including pain treatment. The patients are reassured that they are correctly taking their prescribed medicines, thanks to this monitoring capacity. The possibility of over-prescription of drugs is avoided by this information.Cardiovascular diseases.Digital pills in cardiology also provide the doctor with a precise dose–response curve that shows the patient’s response to a medicine and the time at which the pill was administered. These data can be used in a variety of ways. Thus, the doctor can identify, for example, which people do not respond to the medicine in the tablet. Such patients might be excluded from a study to gauge the therapeutic effectiveness of a specific medicine. This ensures that the trial will only include the participants who have a favorable response to the medicine in question. This development will improve pharmaceuticals’ efficacy and encourage patients to use less ineffective treatments. It might also be used in clinical trials to track the individuals who took their prescription and those who did not.Arterial hypertension remains one of the most common diseases in the developed world. Arterial hypertension triggers a chain of functional and structural changes in vital organs , eventually leading to end-stage disease and the death of the patient .n = 151) [The researchers managed persistent hypertension while receiving chronic anti-hypertensive therapy using the Proteus digital health feedback system  in the NCT02553512 clinical trial (n = 151) . The sysThe invention of WO2018200691 A2 relates to lisinopril compositions with an ingestible event marker  . The curThus, digital pills make it possible for doctors to titrate to the most effective dosages of cardiac medicines by reducing the side effects, such as fatigue of the heart muscle and rebound effects, among others, and changing the dosage and time for each individual patient.Diabetes.Diabetes mellitus is a severe medical and societal issue worldwide. Over the past ten years, the number of diabetes mellitus patients has more than doubled, surpassing 463 million by the end of 2019. The International Diabetic Federation predicts that by 2030, 578 million people will have diabetes, and by 2045, 700 million people will be affected by this disease . Digitaln = 118) with uncontrolled hypertension and type 2 diabetes [The global goal of treating patients with type 2 diabetes is to reduce the cardiovascular risks. In the NCT02827630 clinical trial, scientists evaluated the efficacy of Proteus Ingestible Sensor  to lower blood pressure and glycated hemoglobin in patients  disclosed a therapeutic preparation comprising insulin for delivery into the lumen of the intestinal tract, using a swallowable drug delivery device. In certain implementations, the user may externally trigger the actuating mechanism to administer a medicine via RF, magnetic, or other wireless signaling means, known as an alternative to or supplement to the internally initiated drug administration . MoreoveIn recent years, new technologies for embedding under the skin or attaching to it for continuously measuring sugar levels have come to the market. They are systems that can be connected to other compatible medical devices and electronic interfaces, such as insulin pumps, automated insulin dosing systems, blood glucose meters, and other gadgets used in the management of diabetes.The small intestine’s glucose concentration can be measured using an ingestible device, according to the invention EP3108810 A1  Sa, Les Charbonnières, Switzerland) . The ingThus, along with the patenting of digital pills with ingestible sensors for the treatment of diabetes, there is active patent protection of glucose sensors for indicating the blood and small intestine glucose levels of a patient with diabetes mellitus, and for smart drug delivery.Gastroenterology.Digital pills with ingestible sensors are widely used in gastroenterology. Better treatment regimens are still urgently needed to treat gastrointestinal disorders, such as inflammatory bowel disease. These regimens must be able to deliver therapeutics to specific areas of the gastrointestinal tract, while minimizing or avoiding the negative effects of oral or other systemic administration .Several of Progenity, Inc.’s  patents disclose novel therapeutic strategies for inflammatory gastrointestinal disorders.The inventors of WO 2018/112255A1  described a method of treating gastrointestinal disease with an immunosuppressant that is delivered through an ingestible device . AccordiApplication WO 2018/112240 A1  described the use of a TNF inhibitor to treat a gastrointestinal disease . An ingeProgenity, Inc.  disclosed a targeted drug delivery system for the Il-6r inhibitor , an Il-1When treating or reducing the symptoms of various medical illnesses, the therapeutic medications may occasionally need to be injected into specific regions of the small or large intestine. This is more effective than giving the medicine orally. The therapeutic drugs, for instance, may bypass the stomach’s gastrointestinal tract entirely and be delivered directly to the small intestine. This would make it possible to deliver a higher dose at a specific location inside the small intestine.Along this line, the Drug Delivery System (DDS), developed by the biotechnology company Progenity, Inc. , is of interest for the treatment of the gastrointestinal (GI) tract-related conditions. The applicants of EP3197336 B1  disclosed an electromechanical pill device with localization capabilities . By utilThe inventors  of patent US 8021356 B2 reported a capsule medication administration system . This caIt should be noted that the ingestible sensors also allow for the collection of images and the tracking of luminal fluid and each gut segment’s contents, including electrolytes, enzymes, metabolites, hormones, and microbial populations. Due to the increasing usage of smart phones with Internet connectivity, the users and physicians can readily view and assess online the data produced by this technology.Many ingestible capsules with sensors have been created and are set up to take pictures from inside passages and cavities within a body, such as those passageways and cavities within the GI tract. These gadgets often have an enclosed digital camera along with illumination light sources. Batteries or an external inductive power transfer may be used to power the capsule. Furthermore, the capsule might have a radio transmitter and/or memory for transferring data to an external receiver outside the body .For instance, the inventors and The Smart Pill Corporation ) of application US 2012/0209083 A1 explored the method of using, and determining the location of, an ingestible capsule . An extrHepatitis C.Due to scientific breakthroughs in the treatment of HCV infection, it has been possible to make significant progress in the therapy of this pathology and to actually translate chronic hepatitis C into the category of diseases that are completely cured . n = 253) at a high risk of not adhering to their hepatitis C therapy [Thus, the NCT03164902 clinical trial will evaluate the ability of Proteus digital pills to promote adherence and thus achieve a cure for hepatitis C in the patients  is multi-fold. An effective antiviral therapy with digital pills, leading to the eradication of HCV infection, reduces the risk of progression of the hepatic and extrahepatic manifestations of HCV infection, especially if treatment is carried out before the formation of liver cirrhosis.Without a doubt, digital pills with ingestible sensors have the potential to provide enormous amounts of information in the field of gastroenterology, along with imaging capsules. The dosing devices for releasing medicines into the gastrointestinal tract via one or more sensors are also promising to improve the effectiveness of treatment.Oncology.Health care costs pose a major challenge to national economic welfare. As a result of the aging of the population, the implementation of expensive innovative medicines, methods of radiation therapy and surgery, and diagnostic tests, the cost of treating oncopathologies increases, which is not always justified.In some cases, the effectiveness of innovative, more expensive pills may not be supported by medical evidence, resulting in increased costs without improving outcomes. In the US, the term “financial toxicity” has come into use as a means of describing the financial stress that now often accompanies cancer treatment and reduces quality of life .n = 500) [The researchers conducting the NCT04088955 clinical trial will collect and analyze data on the use of ingestible sensors with capecitabine or supportive medications  and a digital feedback system on medication adherence and data-driven optimization of therapy for cancer patients  taking their tuberculosis medications [The Proteus digital health feedback system  was used in the NCT01960257 study to collect information about patients  are conducted within the NCT01320358 study [The investigations focused on the efficiency of the Ingestible Event Marker  combined with Myfortic (360 mg) in adult kidney transplant patients .By the end of July 2022, search studies were conducted using Internet databases, such as the European Patent Office, the United States Patent Office, the United States Food and Drug Administration , the Lens database, Google Scholar, and The following keywords were used in the patent search: ingestible sensor; digital pill; smart pill; and their combinations.The International Patent Classification and Cooperative Patent Classification were utilized in conjunction with the title, abstract, and claims fields as search terms. When looking for information about patents, keywords are helpful. However, a lot of information is linked to many keywords and their synonyms, which makes analysis time-consuming and challenging. The use of language-neutral patent classification enables focusing the search, making it clearer and faster. Thus, the combined method using the keywords and codes of the International Patent Classification and the Cooperative Patent Classification improves the results of studies examining the patent landscape.Digital products, such as subcutaneous and implantable sensors for continuous glucose monitoring systems, were considered to be outside the scope of this work and are not included in this study.The analysis and systematization of the data made it possible to create the following search query: ((Q1 OR Q2 OR Q3) AND Q4). Q1, Q2, and Q3 are combinations of the keywords, and Q4 uses the International Patent Classification and Cooperative Patent Classification codes that match the digital pills.The patent search results using the keywords: ingestible sensor; digital pill; smart pill; and their combinations, revealed 3101 patents and 1655 simple families.Then, the 3101 patents were analyzed using the International Patent Classification and Cooperative Patent Classification codes (query Q4) to further filter and obtain relevant information. Their codes used in the search are shown in As result, the study altogether ultimately covered 291 patents, including 132 families. The yearly trends of the patent publications, the top 20 owners, the countries participating in innovations, and the key inventors were all studied. The most significant therapeutic application of digital tablets in medicine was identified.Retrospective, logical, and graphic research methods and content analysis were used.The patent landscape analysis shows an increase in the number of patents related to digital pills with ingestible sensors, which indicates the rapid progress and highly dynamic field of digital medicine technologies. The leaders in the number of patents issued are the United States, the European Patent Office, Canada, Australia, and China, which account for 72% of the total number of patents worldwide. The top 20 leading applicants were identified, whose inventions are related to the developments in the fields of mobile clinical monitoring, smart drug delivery, and endoscopy diagnostics.The analysis revealed powerful patent protection for digital pills with an ingestible sensor, with often protection afforded by several patents in some countries, e.g., Abilify MyCite is protected by 32 US patents. This digital pill has six hundred and seventy-one patent family members in forty-one countries.The following main areas of patenting digital pills with ingestible sensors were identified: treatment in the areas of mental health; HIV/AIDS; pain control; cardiovascular diseases; diabetes; gastroenterology (including hepatitis C); oncology; tuberculosis; and transplantology. The problems associated with the rapid implementation into medical practice are technical limitations, medical ethics, the legal framework, and thorough clinical trials of efficacy and safety.Thus, the development of further scientific and practical approaches to the implementation of effective and safe digital pills will improve treatment outcomes, increase compliance, reduce hospital stays, provide mobile clinical monitoring, have a positive impact on treatment costs, and most likely become mainstream for most of the companies in the healthcare sector.


The continuous increase in the production of synthetic plastics for decades and the inadequate disposal of plastic waste have resulted in a considerable increase of these materials in aquatic environments, which has developed into a major environmental concern. In addition to conventional parameters, the relevance of the environmental monitoring of microplastics (MPs) and nanoplastics (NPs) has been highlighted by the scientific community due to the potential adverse effects these materials pose to the ecosystem as well as to human health. The literature has registered an increasing interest in understanding the mechanisms, at the molecular level, of the interaction between NPs and other compounds using molecular simulation techniques. The present review aims to: (i) summarize the force fields conventionally used to describe NPs by molecular simulations; (ii) discuss the effects of NPs in the structural and dynamical properties of biological membranes; (iii) evaluate how NPs affect the folding of proteins; (iv) discuss the mechanisms by which NPs adsorb contaminants from the environment. NPs can affect the secondary structure of proteins and change the lateral organization and diffusion of lipid membranes. As a result, they may alter the lipid digestion in the gastrointestinal system representing a risk to the assimilation of the nutrients by humans. The adsorption of contaminants on MPs and NPs can potentiate their harmful effects on human health, due to a possible synergism. Therefore, understanding the mechanisms involved in these interactions is crucial to predict dangerous combinations and outline action strategies that reduce negative impacts on ecosystems and human health. Depending on the chemical properties of contaminants and NPs, electrostatic and/or van der Waals interactions can be more relevant in explaining the adsorption process. Finally, we conclude by highlighting gaps in the literature and the critical aspects for future investigations. Plastic materials are decisive in several aspects of human life because their physical and chemical properties result in high durability and strength, low production cost, and weight. Nonetheless, its high durability is not without negative effects; even with its great potential to be recycled, tons of plastics become polluting agents in the environment in the course of time. In 2019, approximately 368 million tons of plastics were produced worldwide , but onlThe COVID-19 pandemic has been an aggravating factor in this regard, and, since its beginning, the use of disposable plastics in the health sector has greatly increased. A recent study estimated that in 2020, 1.56 million masks might have ended up in the ocean . Among aSeveral studies prove the bioaccumulation of these particles in living marine life, indicating a direct route for contact with humans through the food chain as shown in the literature review conducted by MPs and NPs with or without adsorbed pollutants, cause adverse effects to several species. The use of molecular simulation techniques, such as molecular dynamics and Monte Carlo simulations, is an alternative strategy to understand the possible health harms due to human exposure to NPs . MoleculMolecular dynamics (MD) is a numerical simulation technique to calculate the thermodynamic and transport properties of many-body systems. The temporal evolution of a set of interacting particles is accompanied by the integration of classical equations of motion. The temporal averages of the trajectories and their fluctuations can be correlated with the macroscopic properties of the studied system . AnotherBoth MD and MC can be applied in understanding the adsorption of pollutants to NPs and studying the interaction mechanism between NPs and biomolecules, such as phospholipids, proteins, deoxyribonucleic acid (DNA), and ribonucleic acid (RNA). Knowing the mechanism involved in these interactions is crucial to predicting dangerous combinations and outlining action strategies that reduce negative impacts on the ecosystems.Despite the potential of molecular simulation to describe the mechanism of interaction between molecules and predict system equilibrium and dynamic properties, it has only been used to analyze systems with NPs and MPs in recent years. Therefore, this review aims to examine how research is being conducted in this area, identify how nanoplastics are being characterized within the molecular dynamics methodology, and to identify and analyze gaps in knowledge. These discussions become important to point out the paths to be followed and the difficulties that need to be addressed more urgently, as well as to guide those who are starting to simulate NPs and MPs while providing an overview for those already working in the area. This review focuses on four points: (i) summarize the force fields conventionally used to describe NP by molecular simulations; (ii) discuss the effects of NPs in the structural and dynamical properties of biological membranes; (iii) evaluate how nanoplastics affect the folding of proteins; (iv) and discuss mechanisms by which NPs and MPs adsorb contaminants from the environment.acs.org, Science.gov, sciencedirect.com, scopus.com, webofknowledge.com, and scienceresearch.com. In total, 706 results were found. Most of the articles were present in more than one of the repositories, thus guaranteeing an unbiased search. After analyzing the documents and excluding duplicates, 28 articles were considered with data that could be used in this review - basically, those that used molecular dynamics and/or Monte Carlo to study nanoplastics. It is interesting to highlight that, due to computational limitations, NPs are generally simulated rather than MPs. However, in many cases, the observations can be extrapolated to systems containing MPs. Meanwhile, there are situations in which the focus of interest is the NP itself.The combinations of keywords used in this research were: “nanoplastics molecular dynamics”, “microplastics molecular dynamics”, “nanoplastics Monte Carlo”, and “microplastics Monte Carlo”. To guarantee a thorough assessment of the literature, the keywords were searched in five different repositories: i.e., a simulation box containing NP, a disparity between simulation times is noted, making a discussion about it worth having. This concern applies not only to studies of NPs through molecular dynamics, but also to any study that use this methodology. The number of scientific articles using the molecular dynamics approach has been growing since 2011, with five published papers from 2011 to 2017 and 23 published papers from 2018 to 2022. Only one paper briefly reported Monte Carlo simulations. Before discussing each point proposed in the study, it is necessary to comment on how research is being conducted in this area, and on important differences between said studies. Initially, it is possible to identify two groups of studies, the first focused exclusively on molecular dynamics, and the second focused on molecular dynamics as a complement to an experimental study or with other models. Within the first group, one can see the time scale used is mainly in the nanosecond range, reaching the microsecond range when using coarse-grained force fields . Within As mentioned previously, Monte Carlo and molecular dynamics can describe particles by pairwise interaction potentials. These interaction potentials are associated with the positions of the particles but also with parameters related to the substance, the particle size, bonds, dihedrals, among others. This information is computed into force fields that can be defined as the functional forms used to describe the intramolecular and intermolecular potential energies of the system. Many are the force fields available in the literature and their modifications, such as OPLS-AA  ; AMBER ; CHARMM We noticed that five studies used some version of the Material Studio program  with theThe most used molecular dynamics simulator to study NP was Gromacs , with 13Regarding the force field only, two publications combined GAFF  and TIP3via molecular dynamics and the force fields used to model NP and water in each of them. A force field development was carried out for polystyrene and polypropylene. It was specially designed for the interaction between these plastics with lipids. In other words, this force field (MARTINI coarse-grained (CG))  is compae.g., ions, nutrients, waste) into and/or out of cells, keeping toxic substances outside the cells as well as separating vital, and often incompatible processes inside the cells  readjusts itself in the presence of nanoparticles of polyethylene with about 5 nm in diameter. The membrane rearranges to cover more of the NP, and the NP surface can rearrange itself to almost double in size in the presence of the membrane. The conformational changes gradually cause the membrane thickness to increase and the average area of each lipid to decrease during the 200 ns course of simulation time. In addition to structural changes, the results show that there are changes in dynamics as well since the presence of NP facilitates lipid movement within the membrane. Thus, it is suggested that the presence of NP has a significant effect on biological membranes , it was possible to simulate up to 2 microseconds in the production stage. The experimental and molecular dynamics results complement each other and lead the authors to believe there is a critical concentration in partial segregation of PS chains within the membrane. Similarly to In the wake of these last two investigations, a recent publication presented experimental and molecular dynamics results, introducing small chains (with 25 styrene monomers) in dipalmitoyl-phosphatidylcholine (DPPC) lipid bilayers . The autThe last study to be covered by this section brings an exciting view of how treating water with chlorine can affect the MPs to the point of increasing the toxicity of these MPs . The autAll studies showed changes in lipid membranes when in contact with NPs or MPs. Considering the biological functions of membranes, it is plausible to conclude that these NPs/MPs somehow affect the cellular environment. All investigations suggested that further investments in this field are needed for proper assessment and control of the potential negative effects of NPs/MPs on environment and human health.Proteins play a substantial role in human health. They are critical for tissue growth and maintenance , and forα-helix composed of 12 alanine adsorbed on hydrophobic surfaces of NP, and mainly for PE and PP, the nanoparticle rearranged to incorporate the peptide, affecting the conformation of the protein, as shown in i.e., the problems caused by exposure to NPs are different depending on their type. This was the first article that had Hollóczi, notably the author of the most publications regarding the study of NPs with molecular simulations, published in said field.Later, In a more recent study, Another study involving NPs and proteins deal with the effect of using PEG spacer on small peptides in a process commonly called PEGylation . This prIn general, the study of interactions between NPs and proteins shows that a single type of nanoplastic cannot be used to understand the possible effects of contacting all types of nanoplastics with proteins. More than one of these studies discussed that polarity is fundamental in how NPs and proteins interact. It is also possible to conclude that this type of study is necessary to indicate new research routes in the subject. Different pairs, peptides, and NPs should be analyzed to understand the problem to a greater. The present number of investigations in this area is still insufficient to provide a general dimension of what must be approached.Research has been conducted to investigate the effects of microplastic as a vector for POP (persistent organic pollutants) contamination in the aquatic environment . MPs ande.g., temperature and pH) and the physical-chemical characteristics of the polymer and the contaminant.Organochlorine pesticides (OCP), polychlorinated biphenyls (PCB), polybrominated diphenyl ethers (PBDE), and PAH are some chemicals that can accumulate on MPs . In addiThe main sorption mechanisms between chemical compounds and MPs/NPs are hydrophobic interaction, electrostatic interaction, pore filling, van der Waals forces, hydrogen bonding, and eraction . ExperimAnother antibiotic that was investigated was the tetracycline hydrochloride and its derivatives (chlortetracycline hydrochloride and oxytetracycline hydrochloride) . The simThe adsorption of three pesticides  on the PE molecular chain with polymerization degree equal to 160 was also evaluated, and interaction energies were found to be statistically the same among them . BesidesRegarding PAH, orptions .2 on PA, PS, and PP was also investigated, and the electrostatic interactions were the dominant mechanism  in an aqueous solution, as well as the influence of PS, PP, PVC, PET, and PE in these systems. Simulations with NP, HA, BaP, and Cu2 + show a competition between HA and BaP to adsorb on NP. When HA wins the competition and adsorbs on NP, it exposes carboxyl groups that offer interesting binding sites for Cu2 + adsorption. The results indicate that PS has the highest capacity of adsorbing BaPs. The motivation to study this system comes from the fact that environmental factors (such as dissolved organic matter - in the article represented by HA) can influence the interactions of NPs and contaminants. Hence the necessity to consider these factors in more detailed studies.There are infinite combinations of pollutants and NPs that humans can contact, and each one can result in different consequences. However, the more studies in this field, the more it is possible to extrapolate behavioral trends. Thus, the investment of resources in this area becomes essential.via molecular simulation can be fitted into the sections above, some address more specific issues. Although most MP/NP studies Archaeoglobus fulgidus (AFEST) and compared the changes in binding energy with plastics. They claimed that modifying an existing enzyme is the best approach, from the biotechnology viewpoint, to solve our plastic waste problem.Following the same train of thought, molecular dynamics and molecular docking appeared in Rhodopseudomonas palustris bacterium) can efficiently depolymerize polylactic acid (PLA) plastic, they sought to understand which amino acids are responsible for this action. The binding affinity data showed that the RPA1511 could also degrade other polyester plastics. These results open doors for the study of more biodegradable plastics.Moreover, Another interesting research was that of Since the presence of NPs in water is a reality, and, with research showing their potentially harmful effects, a line of study arises naturally: the search for methodologies for the removal of NPs from aqueous environments. As far as we could track, the work by The work by Although we initially sectioned this review to manage the study in a more organized way, several other kinds of research were found that do not fit into any of our sections. We can highlight the studies that follow the line of seeking alternatives for removing NPs and MPs from the environment with which humans come into contact, mainly water. It is clear there are numerous ways to approach the problem of NPs and MPs.The present literature review focus on molecular simulation methodologies to study MPs and NPs interactions with proteins, biological membranes, and other contaminants, the force fields used, and the main findings.Most scientific publications are very recent, which strongly indicates that the subject is growing in importance. That is mainly because MPs/NPs released in very high quantities by human activities end up, mostly, in aquatic and marine environments. However, the interactions with and potential impacts on living organisms are largely unknown. All studies regarding the consequences of human contact with MPs/NPs have been hypothetical, while showing that MPs/NPs interact with their surroundings, fundamentally modifying their characteristics.The MD simulation was the most used model out of the methodologies applied, and, based on the results, it fulfilled its objective in showing the interactions at the molecular level. An obstacle, however, is the level of simplification that is necessary during simulation, since natural systems, given their concrete complexities are still outside the reality of investigations on a molecular level. Despite this, simulations can help a great deal to understand experimental data. The use of both experimental and computational approaches is in many scientific reports, and, in their conclusions, the authors have pointed out that they complement each other. As this is a fairly new field of study, there is no good methodology protocol to date on how to simulate NPs. Therefore, the steps in the methodological approaches vary considerably from study to study. Among these differences, one can highlight the simulation time, the force fields applied, the presence or absence of water models, and how the polymer chains are built to be considered NP particles. It is necessary to discuss the validity of certain practices within the molecular simulation to create a more mature protocol based on the information accumulated. In addition to MD, another promising option is the MC methodology. Although many publications presented equilibrium properties that can be accessed through both MC and MD, only one investigation reported the use of MC methodology. Due to how the system reaches equilibrium, MC could be an alternative to achieve simulations with shorter computational times. Between the results obtained, it is interesting to highlight that the interactions between all NPs and the environment cannot be understood through a single nanoplastic model. Depending on the NP type, the interactions, whether with proteins, lipids, or contaminants, are expected to differ significantly. Thus, each NP may cause a different impact when in contact with humans and other living organisms, which makes further studies even more pressing.In future perspectives, it would be also interesting to investigate the effect of NPs in DNA and RNA, and to include the effects of plastic additives on the molecular interactions of MPs and NPs with contaminants and biomolecules.


Molecular Biology and Evolution (MBE). Over the past four decades, the importance of molecular evolution as a research field has grown substantially, encouraged by advances in sequencing technology, new kinds of -omics data, enhanced computational power, and commensurate advances in theories and protocols. The discipline of molecular evolution remains central for understanding the history of life, the processes that shape the diversity of life, and the functional significance of evolutionary change. Our field also has more practical relevance than ever before, because it provides foundational insights into critical societal challenges like the history and spread of pandemics, the evolutionary causes and consequences of human disease, and the biological ramifications of climate change from a molecular viewpoint. Through the decades of change, MBE has kept pace with the remarkable advancements in our field by offering a venue to publish high-quality work that explores evolutionary hypotheses.This year marks the 40th year of publication of As the field has expanded, so has our community. MBE relies on the dedicated service of more than 60 Editorial Board members who volunteer their time and expertise. But community involvement does not stop there: over the past 2 years, the journal utilized the expertise of over 6,000 reviewers to improve the manuscripts of nearly 5,000 authors. Publishing in MBE benefits this extensive community directly, because MBE is an open access, not-for-profit journal. Although MBE relies on author publication charges to fund its editorial and publishing operations, all remaining funds are returned to the Society (SMBE). These funds underwrite SMBE activities, including annual conferences, numerous satellite meetings, and individual fellowships and awards.As the newly appointed co Editors-in-Chief of MBE, we are honored and privileged to serve this vibrant research community. Our foremost goal is to continue to provide a venue for the publication of high-quality science. During our term, we also plan to prioritize initiatives that will broadly serve and strengthen our community, by lowering barriers to publication of quality science and by promoting cooperation and inclusivity among evolutionary biologists.Genome Biology and Evolution (GBE), are now handled by an SMBE committee that is independent of the editorial boards. We intend to strengthen further our relationship with GBE by streamlining the process of transferring manuscripts between journals. In the future, we hope to share additional initiatives with GBE and with other not-for-profit, society-owned journals.Good science should be published irrespective of the authors” ability to pay. We ask authors who do not have funds for article processing charges to submit a waiver request. All waiver decisions for MBE and our sister journal, Among our first actions, we have made the MBE submission process more flexible and straightforward, and we have also initiated a pilot project to consider revisions of previous submissions to other journals with their accompanying reviews. The motivation for considering revised manuscripts from outside journals alongside prior reviews is to lessen the reviewing burden on the scientific community, while ensuring that MBE publishes only high-quality science. We have been exploring additional improvements to MBE, including expanding our social media presence and strengthening our publishing pipelines for Reviews and Protocols, because we believe these have the potential to especially benefit our community. We also hope to find ways to reward reviewers for their services and continue to build an editorial board that reflects the growing diversity of our community as a whole.We cannot close without extending a special thank you to Sudhir Kumar, who has been the Editor-in-Chief for the last decade. Sudhir has served the SMBE community with unusual distinction, and his considerable efforts have contributed to MBE's current strong reputation in our field. During his tenure, the journal increased both the number of submissions and the Impact Factor, which remained strong for 2021 at 8.8. In addition to overseeing the journal, Sudhir has served as SMBE president and organized two SMBE annual meetings. The entire SMBE community owes him our heartfelt gratitude.our scientific community. As members of that community, we are always happy to hear your ideas and to know how we can better serve your needs. Please also join us to celebrate MBE's 40th year this July in Ferrara, Italy for the first in-person SMBE meeting since 2019!Publishing in MBE contributes to its distinguished legacy and benefits


Women with red hair color, i.e., 1–9% of female Europeans, tend to be the subject of various stereotypes about their sexually liberated behavior. The aim of the present case–control study was to explore whether a connection between red hair color and sexual behavior really exists using data from 110 women (34% redheaded) and 93 men (22% redheaded). Redheadedness in women, correlated with various traits related to sexual life, namely with higher sexual desire as measured by Revised Sociosexual Orientation Inventory, with higher sexual activity and more sexual partners of the preferred gender over the past year, earlier initiation of sexual life, and higher sexual submissiveness. Structural equation modelling, however, showed that sexual desire of redheaded women mediated neither their higher sexual activity nor their higher number of sexual partners. These results indirectly indicate that the apparently more liberated sexual behavior in redheaded women could be the consequence of potential mates’ frequent attempts to have sex with them. Our results contradicted the three other tested models, specifically the models based on the assumption of different physiology, faster life history strategy, and altered self-perception of redheaded women induced by stereotypes about them. Naturally, the present study cannot say anything about the validity of other potential models that were not subjects of testing. MC1R gene  indirect, partly or fully active, response of redheaded women to past courtship of potential mates.Based on available scientific literature, we propose five principally distinct possible explanations of the potentially liberated sexual behavior in redheaded women. The hypothetical higher sexual activity of redheaded women could be either the result of their higher sexual desire or of a higher demand on the part of potential mates who prefer redheaded women or believe that redheaded women are more sexually permissive. If higher sexual desire of redheaded women were indeed responsible for their liberated sexual behavior, manifesting for instance in higher sexual activity or early initiation of sexual life, one would expect redheaded women to exhibit one of the following: (1) a difference in physiology, e.g., higher estrogen concentrations; (2) a faster life history strategy, possibly induced by worse health that would shorten life expectancy and likely reproductive period; (3) their altered self-perception with internalized belief in stereotypes about redheads. If the higher sexual activity of redheaded women were the result of higher demand for women with red hair, it could be either (4) a The first model supposes that redheaded women have on average higher sexual desire and sexual activity than non-redheaded women due to some molecular mechanism that affects both the expression of red hair in women and their sexual behavior. The most probable candidate is prenatal estrogen. It has been shown that women with a high 2D:4D digit ratio, which indicates exposure to a higher level of prenatal estrogen , report The second model suggests that higher sexual desire of redheaded women could be due to their switch from a slow to a faster life strategy, which could occur in response to poorer health. Redheaded people, especially women, tend to have worse health  and are The third model proposes that redheaded women have higher sexual desire and are sexually more permissive because the stereotypes about their sexual behavior have altered their self-perception. In this process, an initially incorrect attribution assigned by others can be internalized by the target person who then changes their self-perception to conform to the initially erroneous belief . Based oThe fourth model puts potential mates, usually men, in the active role in explaining the association between women’s redheadedness and their higher sexual activity. If men preferred redheaded women or, based on prevailing stereotypes, anticipated greater likelihood of success in their attempts to have sex with women with red hair, they would do so relatively more frequently. It would automatically lead to a higher sexual activity and a higher number of sexual partners of redheaded women even if their sexual desire was average or even lower than average.The existence of male preference for redheaded women and an evolutionary explanation for it have been suggested already by The fifth model explains the higher sexual activity in redheaded women using the notion of social feedback . In partThe main purpose of this case–control study was to explore whether there is an actual association between red hair color and traits related to sexual life and, if so, to seek a possible explanation. Specifically, we tested five models (see above) which could explain the existence of this association. During the study, we collected data about hair color, sexual behavior, and sexual preferences from 110 women and 93 men with various intensity of redheadedness. We analyzed the association of redheadedness with sexual desire, sexual activity, the number of sexual partners, age at first sexual intercourse, sexual orientation, BDSM  preferences, and sexual dominance. In an attempt to test several hypotheses that could explain the mechanism of the observed associations, we searched for a mediating role of sexual desire and physical disease.The study consisted of a laboratory investigation which took place at the Faculty of Science of Charles University in Prague on September 17, 2018 to October 3, 2018 and subsequent online questionnaire survey performed with the same set of participants within the following few weeks. Information about the experimental design was already described in a study by via Facebook. The study was promoted as a “study of health and personality of redheads” on the timeline of the Facebook page Labbunnies, an approximately 18,000-strong group of Czech and Slovak nationals willing to participate in evolutionary psychology experiments. Anyone could share the link to invitation to the study. Further recruitment of redheaded participants was carried out by invitations on other Facebook pages, selective invitation of registered members of Labbunnies who reported having red hair in our earlier questionnaires , and by handing out flyers in the streets of Prague to people who looked like natural redheads. We invited only people who did not have graying hair and had not dyed or bleached their hair for at least 6 months. The ratio of redheaded participants to controls was intended to be 1:2. In the end, we obtained data from 110 women and 93 men who participated in the study. All provided informed consent. Due to the sensitivity of questions posed to them, participants took part in the study under assigned anonymized codes and were informed about the complete anonymization of the data. Participants received no remuneration, only a commemorative badge and a haircare gift set . The data collection procedure and experimental design, as well as the method of computing aggregated variables, were preregistered prior to the beginning of the study on the website of the Open Science Framework.The recruitment of participants was conducted mostly In the project, redheadedness was determined using several methods: participants’ self-report in the questionnaire, experimenters’ observer report during the laboratory investigation, and two methods of measuring hair pigmentation with a spectrophotometer. A previously published study on the effects of redheadedness on vitamin D concentration, which was performed on the same data, showed that all the above-mentioned indicators of redheadedness correlated very strongly with each other and provided almost identical results . In the All output variables were obtained from the questionnaire data. Sexual desire was computed as the arithmetical mean of Z-scores of three items forming the Desire facet in the Revised Sociosexual Orientation Inventory , namely We also examined a number of potentially confounding variables including sex, age, size of place of residence  and current sexual partnership status . Physical disease was calculated as the arithmetical mean of Z-scores of responses to the number of antibiotic treatments a respondent used in the past year, the number of different kinds of drugs prescribed by a medical doctor which a respondent uses daily, the number of different kinds of non-prescription drugs or food supplements a respondent uses on a daily basis, the number of visits to a general practitioner in the past year, the number of different medical specialists a respondent visited in the past year , and the intensity of physical health problems . Similarly, mental disease was computed as the arithmetical mean of Z-scores of responses to the intensity of suffering from anxieties, depressions, manias, obsessions, phobias, visual hallucinations, auditory hallucinations, burnout, and headaches, and the intensity of mental health problems . Physical and mental disease were calculated from variables used for the computation of indices of physical and mental health problems in several previously published studies . VariablBefore statistical analyses, we filtered out records of three subjects who had gray hair or did not provide information about their age. When a respondent omitted over 20% of questions relevant for one index , we did not compute the index for this subject and excluded their data from particular tests. In case missing data accounted for under 20% of variables relevant for a particular index, that index was calculated from the remaining variables. The percentage of excluded cases from the tests including sexual desire, BDSM index, and the index of sexual dominance were 1, 12, and 11%, respectively.The age of women and men was compared using the Wilcoxon test. Associations of all focal variables with sex and age were examined by the non-parametric Kendall correlation test. Associations of all focal variables with potentially confounding variables  were analyzed by a partial Kendall correlation test with age as a covariate.In theory, the effect of redheadedness on traits related to sexual life need not apply only to women. Therefore, we have initially fitted generalized linear models (GLM) with redheadedness, sex, age, and interaction between redheadedness and sex as predictors. Redheadedness was set as an ordered categorical predictor, while sex was a binary variable and age was on a pseudo-continuous scale. Each dependent variable was ascribed to a family based on a visual inspection of density plots and histograms. We have also considered the distribution that would be most likely based on the expected data-generating process. For example, in case of the number of sexual partners of the preferred sex, we expected this variable to demonstrate a Poisson distribution. In the case of non-heterosexuality, we expected the variable to be binomially distributed. To include the effect of subjects who reported not having had their first sexual intercourse yet, we conducted a survival analysis, namely the Cox regression . Prior to the Cox regression, independent variables were standardized by computing Z-scores and redheadedness was set as ordinal. The Cox regression model also included redheadedness, sex, interaction redheadedness–sex, and age as predictors.Because the tested hypothesis about the effect of redheadedness on traits related to sexual life concerned women, we have subsequently analyzed women and men separately. We tested associations between redheadedness and traits related to sexual life using a partial Kendall correlation test with age as a covariate. In the next step, we used the same test with age and potentially confounding variables that had a significant effect on the output variables as covariates.To investigate the role of potentially mediating variables in the association between redheadedness and sexual behavior, we performed structural equation modelling, in particular path analyses. Prior to path analyses, multivariate normality of data was tested by Mardia’s test. Since the data was non-normally distributed, and redheadedness, sexual activity, and the number of sexual partners of the preferred sex were set as ordinal, parameters were estimated using the diagonally weighted least square (DWLS) estimator. When comparing nested models, we considered changes in fit indices, such as the comparative fit index (CFI) and the root mean square error of approximation (RMSEA). To establish invariance between models, the following criteria had to be matched: ΔCFI < −0.005 and ΔRMSEA <0.010 .https://doi.org/10.6084/m9.figshare.21200968.v1. R script containing the GLMs, Cox regression and path analyses is likewise published on the Figshare at https://doi.org/10.6084/m9.figshare.21201004.v1.To assess the strength of the observed effects, we used the widely accepted borders by p < 0.001). On a six-point scale of self-reported redheadedness, 37 (33.9%) women and 20 (22%) men responded 4 and higher. Descriptive statistics for all variables are presented in The final set consisted of 109 women  and 91 men . The age of women and men differed significantly . Many focal variables significantly correlated with sex and age. For instance, women had more intensively red hair than men and redheadedness correlated negatively with age. Regarding other potential covariates, current sexual partnership status was significantly associated with four out of seven variables related to sexual behavior. Size of place of residence, physical disease, and mental disease did not exhibit many significant associations with predictors and output variables see .p < 0.001) and associated positively with redheadedness . Interaction between redheadedness (linear trend) and sex was not significant in this model . In the second model for sexual activity, redheadedness also had a significant linear effect . There also was a significant interaction between the linear effect of redheadedness and sex , suggesting that the overall positive effect of redheadedness on sexual activity is driven mainly by the effect in women . The increase in redheadedness was associated with a linear increase of 1.77 in the number of sexual partners of the preferred sex. In this model, there was no significant interaction between redheadedness (linear trend) and sex . In the fourth model, which modelled non-heterosexuality, none of the predictors  was significant . In the fifth model, the index of sexual dominance was significantly predicted only by sex , suggesting that men are more dominant. In this model, we have also observed a non-significant linear trend of the association between redheadedness and the index of sexual dominance . The interaction between redheadedness (linear trend) and sex was not significant . The model for BDSM index revealed no significant effect of any predictor .Initially, we analyzed the effect of redheadedness on variables related to sexual life with GLM. In the first model for sexual desire, there was a significant linear effect of redheadedness and a significant effect of sex. Sexual desire was significantly higher in men . There was also a significant positive quartic (^4) spline in the model , suggesting that the association between age at first sexual intercourse and redheadedness was not linear and increased with a higher level of redheadedness. The interaction between redheadedness (linear trend) and sex was not significant in this model .In our dataset, 10 (9.2%) women and five (5.5%) men reported they had not yet had their first sexual intercourse. We have thus performed a Cox regression to include the effect of those subjects. Redheadedness (as a linear trend) showed a significant effect on the likelihood of having first sexual intercourse , sexual activity , and the number of sexual partners of the preferred sex , and negatively with age at first sexual intercourse  and the index of sexual dominance . These results represent strong and medium effects  or with the BDSM index .The GLM found significant effects of redheadedness on certain variables related to sexual life and in one model also a significant effect of the redheadedness–sex interaction. Therefore, we have subsequently also analyzed women and men separately with partial Kendall correlation controlled for age. In women, redheadedness positively correlated with sexual desire . The results for both sexes remained qualitatively the same after correction by Benjamini-Hochberg procedure.In men, redheadedness showed no significant correlation with any variable related to sexual life . For men, the results remained non-significant.Current sexual partnership significantly correlated with sexual activity, the number of sexual partners of the preferred sex, non-heterosexuality, and BDSM index . We haveSensitivity power analysis for the female set  showed that the smallest detectable effect was Pearson’s r = 0.28, which corresponds to Kendall’s τ = 0.18. For the male set , the smallest detectable effect was Pearson’s r = 0.33, which corresponds to Kendall’s τ = 0.21.The higher sexual activity of redheaded women could either result from their own higher sexual desire or be the consequence of potential mates’ higher demand for redheaded women . If the former is true, and higher sexual activity of redheaded women is the result of their own higher sexual desire, then it should be mediated by their higher sexual desire, while if the latter is true, sexual desire does not play a mediating role and the intensity of sexual activity in redheaded women is not associated with a higher intensity of sexual desire on their part. To discriminate between these two possibilities, we studied the effect of redheadedness on sexual activity and the number of sexual partners of the preferred sex using path analyses with sexual desire as a potentially mediating variable. In order to also test the hypothesis about higher sexual desire of redheaded women being a part of a faster life strategy (see Introduction), we included physical disease and age into the structured models.In women and men considered together, redheadedness had a direct positive effect on both sexual desire and sexual activity . The dirp = 0.28). Path analysis showed no effect of redheadedness on physical disease in either sex, and the data thus provided no support for the hypothetical explanation based on adoption of a faster life strategy. Worse health had a negative impact on sexual activity only in men.Because the GLM revealed that the effect of redheadedness on sexual activity depends on sex, we have repeated the analyses separately for each sex. The models for women showed the same pattern as the models for both sexes ,C. RedheThe results of this study showed that the intensity of redheadedness is associated with shifts in sexual behavior, especially in women. Women with red hair color exhibited higher sexual desire and sexual activity, a higher number of sexual partners of the preferred sex, earlier initiation of sexual life, and lower sexual dominance . However, one model for men also showed a positive effect of redheadedness on sexual desire.Our results are in accordance with recent findings of The higher sexual activity of redheaded women was not mediated by their higher sexual desire and the mediating effect of sexual desire in the association between redheadedness and number of sexual partners was weak. These observations thus do not support the first, second, and third model explaining sexual behavior in redheaded women (see Introduction). It would seem that the fact that women have red hair more frequently than men do and, according to our data, exhibit more liberated sexual behavior more often than men do might support the first model, which suggests the role of a molecule, e.g., prenatal estrogen, that would affect both women’s hair color and sexual behavior. This model also seems to find support in our results which show that redheaded women express higher sexual submissiveness, because the intensity of submissiveness is associated with a higher 2D:4D digit ratio that indicates exposure to prenatal estrogen . But if On the other hand, sexual desire is not the only one possible motive for active initiation of sexual activity (see limitations in Discussion below). It is well possible that higher sexual desire – in consequence of prenatal estrogen or another intrinsic factor, e.g., on the level of neurotransmitters or hormones – in combination with another motive for having sex specific to redheaded women could explain why redheaded women are more sexually active. This subject, however, requires further investigation.lower sexual activity and having fewer sexual partners . The stereotype about higher sexual permissiveness of redheaded women seems to be widespread among Czech and Slovak men see . In redhTo test this model in the future, it would be useful to explore the sexual behavior of women who have red body hair but are not redheaded. This would differentiate between active sexual behavior of women with red hair on the one hand and behavior that is a passive consequence of mating efforts of potential suitors and prejudices about redheaded women on the other hand. We could not conduct this investigation because our sample unfortunately contained only six non-redheaded women with red body hair. Another useful approach would be to test whether naturally non-redheaded women with their hair and eyebrows dyed red are approached by men more often than when they wear their natural hair and eyebrow color. To test the proposed explanation according to which the prevailing stereotypes about more permissive redheaded women could be responsible for the observed association, future studies ought to explore men’s motives for approaching redheaded women as well as the motives of women with other hair colors for having sex.Our analyses do not support the third model, which aimed to explain higher sexual activity and sexual desire in redheaded women by their changed self-perception. Because higher sexual desire did not mediate sexual activity in redheaded women, it is unlikely that their increased sexual activity is due to an altered self-concept that incorporates an internal conviction about the validity of stereotypes about permissive redheads. In the present study, however, we collected no data on redheaded women’s self-perception. As mentioned above, it is also possible that redheaded women have other motives for their more liberated sexual behavior apart from sexual desire – and these motives could be part of their self-concept.We could neither prove nor disprove the fifth model, which suggests that the higher sexual activity of redheaded women is the result of a mechanism of social feedback. Based on our results, redheaded women might, in response to earlier experience with mating efforts, mostly made by males, consider higher sexual activity a social norm and react more positively in interaction with potential mates or even initiate sexual activity themselves. But to decide whether this mechanism applies, one would have to explore women’s individual motivations and opinions related to sexual behavior exhibited by women with and without red hair.Although large cross-sectional internet studies showed worse health of redheaded individuals , our datThe main limitation of this study is that the participants did not form a random, representative sample of the Czech population. We suppose that subjects who took part in the laboratory investigation may have been exposed to a sieve effect, forming a group of rather altruistic, active people in good physical and mental condition. On the other hand, whenever people have the option of refusing to participate in a study, that is, in all studies performed in accordance with the widely accepted ethical standards, the issue of non-representativeness of a sample is always present. In any case, the observed results should be verified in future by using some more representative data, for instance collected by an internet questionnaire, or by repeating the study on other samples that would not be self-selected for better health or altruism.Another problem of the present study is the relatively low number of male participants, which may have led to false negative results for some analyses on this subset. Most associations observed in men were non-significant and the size of all effects was lower than in women. On the other hand, the size of many formally non-significant effects was relatively high, and one path analysis model for men revealed a significant positive effect of redheadedness on sexual desire. The absence of evidence of the effects of redheadedness in men therefore should not be interpreted as a non-existence of those effects.It is fair to mention some limitations of the statistical methods used in this study. As mentioned above, the absence of statistical evidence for the existence of an effect is not a proof of its non-existence. Specifically, the path analysis did not find any evidence of a mediating role of increased sexual desire in the effect of redheadedness on sexual activity. In fact, the strength of the indirect (mediated) effect of redheadedness on sexual activity was much lower than the strength of the direct one. However, the observed differences in the strengths of direct and indirect effects could be caused not only by a real difference in effect strengths but also by differences in the precision of measurement of variables in the model. If, for example, women were willing to truthfully report the frequency of their sexual activity but reluctant to truthfully report the intensity of their sexual desire, then any statistical method, including path analysis, would necessarily underestimate the power of any mediating effect of sexual desire.Finally, it should be noted that we tested the validity of just five models from a much larger set of all theoretically possible models. Our study seems to contradict three models and to support the other two, which naturally does not prove their validity. In fact, it is well possible that some model we did not test could be responsible for the observed associations. Specifically, sexual desire is not the only proximate reason for active initiation of sexual activities. There are many other own motives for having sex beyond sexual desire, including stress reduction, experience seeking, self-esteem boosting, striving to increase social status, seeking revenge, pursuit of resources, or pursuit of practical benefits . In thisThe results of this study suggest that redheaded women exhibit higher sexual desire, higher sexual activity, higher number of sexual partners, an earlier initiation of sexual life, and a higher level of sexual submissiveness. However, sexual desire does not seem to mediate the more liberated sexual behavior in redheaded women in our data. We therefore propose that an explanation of the observed association between redheadedness and certain characteristics of sexual behavior in women might be found in the stereotypical social labelling of redheaded women as being more sexually permissive, which might encourage potential mates to try and have sex with them. In the process of forming this association, redheaded women can either affirmatively respond to the courtship of potential mates or, alternatively, consider frequent sexual activities a social norm and actively initiate sexual interactions themselves. Given the lack of data regarding women’s motives for having sex and men’s motives for approaching redheaded women, we cannot consider this explanation definitive. It should be borne in mind that sexual desire is not the only one possible motive for active initiation of sexual activities. Other legitimate candidate explanations include the concentration of prenatal estrogen, faster life strategy (possibly induced by unfavorable conditions in childhood) or redheads’ own internal belief in stereotypes about themselves. Aside from that, there are other possible models which were not considered in the present study. Given the probably non-representative sample on which this study is based, our observations should be generalized with caution and our conclusions viewed rather as working hypotheses whose predictions should be tested in future, specifically designed studies.https://doi.org/10.6084/m9.figshare.21200968.v1.The datasets presented in this study can be found in online repository. The names of the repository/repositories and accession number(s) can be found at: figshare: The studies involving human participants were reviewed and approved by Institutional Review Board of the Faculty of Science, Charles University. The patients/participants provided their written informed consent to participate in this study.KS designed research, collected and analyzed the data, and wrote the manuscript. VF collected and analyzed the data and revised the manuscript. JH and ŠK collected the data and revised the manuscript. JF designed research and participated in the interpretation of results and writing of the manuscript. All authors contributed to the article and approved the submitted version.This study was supported by the Grant Agency of Charles University (project numbers 1494218 and 1310120) and Charles University Research Centre program (No. 204056).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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Many women in detention are mothers and often the sole caregivers of their children. Italy, as most European countries, allows mothers to keep their children with them in detention, with the aim of preserving the fundamental bond between mother and child. Since prison does not seem to provide a good environment for the child’s growth, there are different alternative residential solutions, such as Group Homes. The aim of this preliminary study was to explore the differences between mothers living in detention through alternative measures with their children and mothers who are not detained regarding parenting stress, child behavior from the parent’s perspective, and maternal attachment. Twelve mothers were enrolled in this study, divided equally between the detained and the control groups. Both groups’ participants completed a three-questionnaire battery in order to assess parenting stress, child’s behavior, and maternal attachment. The analyses of variance showed significant differences between the two groups, with the detained group reporting higher scores than the control group in almost all the subscales of parenting stress. The results highlighted that imprisoned mothers might experience more stress than the general population. There is a need to design intervention programs to support parenting in detention. Although, as of today, the female population represents a small portion of the total number of incarcerated people in Europe and across the world, this is increasing every year . Many woIn Italy, as in most European countries, Law No. 354 of 26 July 1975 allows incarcerated mothers to keep their children with them, under special circumstances, until the age of three. The aim is to preserve the dyadic mother-child fundamental bond from birth .Given these opinions, there are data resulting from different studies to consider.First, it seems reasonable to expect mothers in detention to feel powerless, to experience distress regarding their role, and stress related to deprived conditions ,10,11.Second, the negative outcomes for children associated with parental imprisonment have been well documented by researchers ,12. ChilIn addition, multiple studies conducted in the US have found that the reduced contact between mother and child during imprisonment may exacerbate attachment disorders and damage the developing attachment bond ,16,17. AAll consequences and effects cited above led the Italian Legislative system to reconsider accommodations for imprisoned mothers. Thus, in 2001, Law n. 40 made it possible for imprisoned mothers to serve their sentences through three alternative measures of detention, allocated in appropriate facilities . The firAlthough alternative solutions to prison exist, in the literature, there is a lack of data regarding their possible effects on the quality of mother–child relationships. It appears to be important to provide preliminary evidence about the impact of alternative measures of detention by comparing a group of women in detention through alternative measures with a group of mothers who are not detained. Therefore, the aim of this preliminary study was to explore the differences between mothers living in detention through alternative measures with their children and mothers who are not detained regarding parenting stress, child behavior from the parent’s perspective, and maternal attachment. Our first hypothesis was that mothers currently detained through alternative measures would experience higher levels of stress compared to mothers not in detention. A second hypothesis was that children living with mothers detained in alternative measures facilities would report higher levels of difficult behavior because of the delicate living conditions. The third hypothesis was that maternal attachment would be higher in women detained in alternative measures facilities, presumably because of a greater protective instinct.This study was approved by the Ethics Committee of the Department of Dynamic and Clinical Psychology, and Health Studies of the Sapienza University of Rome.M = 35.0; SD = 7.6 years old) were recruited.After reading and signing the Informed Consensus, 12 mothers  , a questThe second questionnaire used was the Eyberg Child Behavior Inventory (ECBI) , a 36-itThe third questionnaire used was the Maternal Attachment Inventory (MAI) , which iThe questionnaires were of a self-report nature, but it is important to underline that some women of the detained group were unable to understand the meaning of some items fully, so it was necessary for the researcher to read and explain the questions to the participants. In the control group, women completed the surveys in a self-report form.In order to analyze the difference between the two parenting conditions (home detention and free living), analyses of variance (ANOVAs) were performed, with Group (detained vs. control) as the between-group factor, on the scores of parenting stress (PSI-SF), child behavior from the parent’s perspective (ECBI), and maternal attachment (MAI).Analyses were conducted using the “Statistica8” software ., to assess the differences in parenting stress (PSI-SF), child behavior from the parent’s perspective (ECBI), and maternal attachment (MAI). The main effects of the detention situation were reported on the PSI-SF score for total stress, dysfunctional mother–child interaction, difficult child, and defensive responding, with the detained group reporting higher scores than the control group. There were no significant differences between the two groups for ECBI and MAI scores. The results of the questionnaires are summarized in The descriptive statistics of the participants were reported in The aim of this preliminary report was to explore the differences between mothers living in detention through alternative measures with their children and mothers who are not detained regarding parenting stress, child behavior from the parent’s perspective, and maternal attachment.As hypothesized, the main finding showed significant differences in the levels of parental distress between the detained mothers and the control ones. In particular, compared to the control mothers, mothers under alternative measures of detention reported higher levels of dissatisfaction concerning interactions with the child and higher disapproval of the child’s behavior. Moreover, mothers detained through alternative measures reported higher negative perceptions of the child’s capability for emotional regulation and a greater attitude toward denying or minimizing the difficulties associated with parenting. These findings suggest that mothers in alternative detention would experience higher levels of distress, as expected. Although the alternative measures of detention, such as Group Homes and home detention, are aimed at supporting parenting, in this preliminary report, the mothers in detention experienced a higher level of distress than those who are not in detention. This is in accordance with the current literature, as mothers in detention in other countries, such as in the US, were reported to display higher levels of stress compared to the general population ,10,11,28Despite the fact that children living in alternative measures facilities did not exhibit higher levels of dysfunctional behaviors compared to the control group, these results have likely been influenced by the limited sample size, and it might be possible to observe such differences when working with larger samples. This seems to be supported by a trend in the ECBI’s numbers, suggesting higher levels of dysfunctional behaviors among the detained group in comparison to the control group. While there are no studies in the current literature that concern behavioral functioning in children living in alternative measures facilities, it is known that children who live in prison with their mothers in Italy frequently suffer from sleep disorders, inappetence, apathy, and restlessness . More brThe analyses did not show any significant differences in maternal attachment between the two groups in the Maternal Attachment Inventory scores (MAI)  Table 2Table 2. It is known that the adoption of the role and the identity of the mother starts with pregnancy and continues with early motherhood. This process could be affected by environmental precarity and personal adversity , suggestDue to the lack of research concerning mother–child attachment in the context of detention through alternative measures, more studies are needed to comprehend how the imprisonment experience can affect maternal attachment and identity.Overall, the study presented several limitations. Primarily, the size of the sample was small. Although 12 subjects can be sufficient to conduct an exploratory study on a topic that is scarcely investigated, data analyses are limited in generalizability, diversification, and impact. In addition, the age range of children (2–12 years) considered in the present study was quite broad and could potentially lead to discrepancies in the interpretation of the results, considering the specificity of the developmental stages that occur during these ten years. Further studies should monitor this variability to verify the effect of developmental stages on mother–child relationships in detained conditions.Moreover, the questionnaires used to carry out this study were not adequate regarding the characteristics of the detained group of the present study, probably due to the gap concerning the language skill between the two groups. Indeed, in the detained sample, five out of six women were not able to complete the administration through the self-report mode because they did not fully understand the meaning of some items; therefore, the experimenter had to read and explain the questions to each one of them.Previous studies suggested that the level of schooling and literacy is a very important factor affecting performance on tests in general, especially on cognitive tests . HoweverAnother limitation of the present study was the social desirability bias that was presumably more present in the detained group.The detained group can be defined as a niche within a niche since they were primarily incarcerated mothers, and secondly, five out of six women were of Roma ethnicity. As far as it has been possible to observe, detained women living with children in Italian prisons are mainly from the Roma community . In EuroRegarding the practical developments of this preliminary study, it should be noted that there is a strong social need to raise awareness on the topic. In fact, many people are not aware of the existing conditions of detained mothers living with their children and, more broadly, of their relationship dynamics and of the related social implications.The inexistence of research tools validated for ethnic and social minorities contributes to fueling social and ideological distancing towards those minorities in contemporary society that could be filled by the scientific community.In conclusion, the findings of the present preliminary report show that mothers living in alternative measures detention facilities are more stressed than mothers not in detention. In particular, when compared to control mothers, mothers detained in alternative measures facilities reported higher levels of dissatisfaction concerning interactions with the child and higher disapproval of the child’s behavior. Moreover, mothers detained in alternative measures facilities reported higher negative perceptions of the child’s capability for emotional regulation and a greater attitude toward denying or minimizing the difficulties associated with parenting. These findings suggest that mothers in detention experience higher levels of distress in general.These findings suggested planning studies to verify the psychological impact of alternative detention on the well-being of mothers and children. It seems necessary to design intervention programs to support parenting in prisons, ICAMs, residential homes, and protected Group Homes ,19. The