Neuropathic pain affects 7–10% of the population, with most of the patients receiving inadequate and incomplete treatment. Owing to the high financial burden and the poor quality of life of the patients and their caretakers, there is a dire need to address the challenges in diagnosing and treating chronic neuropathic pain.  This literature review was conducted to review novel treatments and related challenges through a systematic search from sources such as PubMed, Google Scholar with the combination of MESH words such as neuropathic pain, management of neuropathic pain. Articles from non-English literature, reports without human subjects, animal studies, and abstracts/posters were excluded. However, human studies and studies published in English were included.  This review article discusses novel treatment modalities while acknowledging the challenges medical workers face while encountering neuropathic pain. Despite the recent advances in diagnosis and treatment modalities, several challenges still exist. Hence, there is still a need to explore the various treatment modalities, emphasizing the cause and underlying pathophysiology of neuropathic pain.  We recommend integrated multimodal treatment with the current treatment facility, including various medical disciplines. However, a personalized approach would work the best depending on the 'patient's medical history. Therefore, this article recommends an integrated, cause-specific, cost-effective approach to address this problem of chronic neuropathic pain. The lacA GABA analogue that has analgesic effects on all subtypes of neuropathic pain and can improve interference of neuropathic pain with activities of daily living . In a ra2 improves vascular function by restoring NO bioavailability and mediating vasodilation resulting in potential effectiveness as a therapeutic agent in diabetic peripheral neuropathy and endothelial dysfunction [Oral formulation of NaNOfunction . In a dofunction . The NPSfunction . In addifunction .Lipoic acid, a potential antioxidant, improves diabetic neuropathy by improving blood flow, reducing oxidative stress, and improving distal nerve conduction . A prospLidocaine, a widely used local anesthetic and class Ib antiarrhythmic, has effectively treated neuropathic pain . A prospAV-101 (l-4 chlorokynurenine): it is a novel oral agent which is converted into a potent, selective GlyB site antagonist of the NMDAR, and demonstrated to be active in neuropathic pain . The ranP-value 0.0001) [Turpentine oil is a safe topical analgesic and skin protectant observed to relieve neuropathic pain . A rando 0.0001) .1 and CB2 receptors resulting in a wide range of medical indications, including analgesia [Dronabinol is a purified active compound of medical cannabis, which acts primarily upon CBnalgesia . A randonalgesia . In addinalgesia . This trnalgesia .μg/kg for lumbosacral radiculopathy [Neublastin targets proteins that belong to a group of glial cell-derived neurotrophic factors that act on sensory neurons and assist in the regeneration of sensory nerve cells relieving neuropathic pain . Study dulopathy . Approxiulopathy .It binds to presynaptic cholinergic nerve terminals and decreases the release of acetylcholine, causing neuromuscular block . A randoμg had 50% of participants with pain relief (3/10) but had high dropout rates in trials with chronic low back pain [μg reported adverse effects during titration and discontinuation of the drug [This opioid alternative analgesic that combines nociceptin/orphanin FQ peptide (NOP receptors) receptor reduces afferent neuronal excitability, a critical pathway for pain transmission . The cliack pain . In addithe drug . Dizzinethe drug .α3) co-receptor [A protein in the glial cell line-derived neurotrophic factor (GDNF) family, BG00010 is a selective ligand for the GDNF family receptor alpha-3  and cannabidiol (CBD), may be effective in improving MS-related neuropathic pain . This isThe assessment of the efficacy and safety of an alternative route of administration of ketamine, an open-label trial, showed that subjects who applied topical ketamine 10% three times a day for two weeks had a decrease in their numerical pain scale by the end of two weeks, ranging from 14% to 63% . No adveNonpharmacological pain management methods for chronic neuropathic pain proved to be valuable in a multimodal approach, combined with pharmacotherapy concurrently or separately , 61.Although usually invasive, neurostimulation techniques provide effective pain control in patients with chronic neuropathic pain due to paraplegia and above-knee amputation , 62. NeuIt is known to be a safe, efficacious, therapeutic option for chronic neuropathic and drug-resistant pain. Neurosurgeons specifically prefer it for such cases . In addiIt was a commonly used invasive technique for pain relief of various neuropathic pain conditions. It works through the stimulation of the dorsal columns of the spinal cord by administering electrical impulses at frequencies of approximately 50 Hz (by an implanted pulse generator-PG) and the electrodes (or lead). It can suppress the central neuronal hyperexcitability with a remarkable reduction of pain intensity scores. Despite being well known for a relatively lower side effect profile such as excessive sedation or cognitive impairment, SCS has been associated with serious adverse events such as infection, dural puncture leading to a subdural hematoma, and subsequently death in one of the patients , 65. NevIt is used to treat neuropathic pain in post-peripheral nerve injury, post-spinal cord injury, brain stem disease and thalamic pain, pain after amputation, either phantom or stump, cranial and facial pain, including anesthesia dolorosa, and plexopathies. DBS trials with lead externalization have been used extensively over the last 50 years to treat chronic pain. However, spinal cord and/or peripheral nerve stimulation have overshadowed DBS in the pain arena. Laser thermal ablation and radiosurgery provide cost-effective, efficacious therapy and an ablation-based alternative to DBS, possibly used with magnetic resonance imaging guidance to resolve neuropathic pain, especially in advanced stages of cancer .It has been proven to be helpful in the treatment of several chronic pain conditions, including peripheral nerve dysfunctions, complex regional pain syndrome, and cranial neuralgias. These peripheral nerve stimulators allow external pulse generators to transmit impulses wirelessly to the implanted electrode, and their implantation is lesser invasive. Lately, TIMWAVE, Bioness, and SPR Therapeutics have produced a new generation of devices that allow for external pulse generators to transmit impulses wirelessly to the implanted electrode. In a study conducted by Mobbs et al., significant improvement in symptoms and lifestyle quality was reported post-implantation of peripheral nerve stimulators;  while DeTranscutaneous electrical nerve stimulation (TENS) is an expensive, non-invasive, self‐adhesive to relieve pain in CNP, PNP, complex regional pain syndrome, phantom limb pain, and fibromyalgia . The admThese devices deliver therapeutic electrical stimulation, often at very high frequencies, to different parts of the body. Techniques for chronic pain are being developed, including epidural stimulation and vagal nerve stimulation, which can be quite invasive and expensive. In addition, the analgesic mechanisms of TENS can be evaluated with advanced neuroimaging techniques, such as electroencephalography, magnetoencephalography, and magnetic resonance imaging .The use of implanted epidural stimulation to treat persistent, drug-resistant neuropathic pain has been proposed. Various investigations have shown that recurrent transcranial magnetic stimulation (rTMS) administered to the motor cortex can reduce neuropathic pain, at least temporarily . AdditioIt is a recently developed, non-invasive, painless brain stimulation treatment that uses direct electrical currents to stimulate specific brain parts. MRI-guided transcranial focused ultrasound is a nascent, minimally invasive method of targeted tissue thermal ablation that may be used to treat central neuropathic pain with current and potential intracranial applications. Transcranial magnetic-resonance-imaging-guided focused ultrasound is a very precise and a radiation-free neurosurgical technique for treating neuropathic pain . In addiRemote electrical neuromodulation has proven to be a novel acute treatment modality for migraine by stimulating the upper arm peripheral nerves to induce conditioned pain modulation (CPM) . This teTherapy, an emerging technique, has not been made widely available yet as the equipment is expensive and possibly challenging for clinicians, especially those with limited technological experience. However, with the development of “plug and play,” low-cost IVR devices such as the Oculus Rift, Gear VR, and Google Cardboard, IVR no longer requires such specific technical proficiency. Therefore, IVR may be a feasible and affordable option for adjuvant therapy of neuropathic pain. A preliminary study was conducted to review the application of a new virtual reality method and 3D augmented reality mirror visual feedback therapy in persistent, unilateral upper extremity neuropathic pain, and a significant reduction of pain was reported .It is a novel, nonpharmacological intervention for neuropathic pain wherein a single-pulse electrical stimulation (EStim) was delivered transcutaneously to a peripheral nerve study.It is a novel form of superficial neuromodulation, electro-analgesia therapy for non-invasive pain relief in chronic neuropathic and cancer pain, based on a new generation of medical devices that use a rapidly changing electrical impulse to send a “non-pain” signal along the same pain fibers that are sending the “pain” stimulus. This is predicted to potentially treat chronic neuropathic pain and cancer pain resistant to opioids. Scrambler Therapy was created to trap C-fibers and relieve neuropathic pain, but it has also been shown to help with numbness and tingling caused by various nerve fibers , 82.It is an upcoming alternative strategy to reduce pain using genetically encoded and optically active proteins, opsin, to control signaling events by directly manipulating somatosensory pathways. Evidence from animal models shows that optogenetics is an efficient approach to alleviating inflammatory and neuropathic pain. Considering that gene therapy techniques are already at the clinical stage for several pathological conditions, analgesia by phototherapy could be a promising strategy to treat chronic pain .Management of patients with painful diabetic peripheral neuropathy (PDPN) is done by photon stimulation delivered using LEDs. Photo biomodulation or low-level laser therapy (LLLT) utilizes electromagnetic technology, which significantly improves the quality of pain and QOL outcomes in patients with a significant amount of pain and disability due to diabetes . Further3.6.6. Vibration Stimulation: (WBV) has recently been shown to improve strength, balance, endurance, and blood and lymph fluid circulation in patients with stroke and peripheral neuropathy associated with Parkinson's disease . WBV impProposed molecular modalities for treating chronic neuropathic pain include ion channel expressions, immune reactions, and inflammatory substrate diffusions. Recent advances in RNA sequence analysis have discovered specific ion channel expressions in nociceptors such as transient receptor potential (TRP) channels, voltage-gated potassium, and sodium channels. G protein-coupled receptors (GPCRs) also play an essential role in triggering the surrounding immune cells. Multiple protein expressions are thought to complicate the therapeutic development of neuropathic pain. Recent progress in optogenetics and pharmacogenetics may herald the development of novel therapeutics for incurable pain. Optogenetics and designer receptors exclusively activated by designer drugs (DREADDS) provide hope in controlling intractable pain in patients suffering from debilitating neuropathic pain. Based on the underlying cause of neuropathic pain, it may be possible to improve pain management by using a combination of therapies and drugs targeting specific molecular targets. With continued development and refinement of this technique combined with viral vector-mediated safe and efficient gene therapy, there is a hope to develop a satisfactory treatment for otherwise intractable neuropathic pain .This is a new approach to repair damaged nervous system-induced neuropathic pain syndromes rather than simply providing palliation. Stem cells offer a totipotent cellular source for replacing injured or lost neural cells. Stem cells have the ability to stop degenerative processes, suppress apoptotic pathways, and let wounded and uninjured nerves survive and regenerate. The ability of stem cells to change cellular processes, when combined with their ability to release neurotrophic factors, creates a protective and restorative milieu that has the potential to reverse the source of neuropathic pain. Stem cells can play many functions in the damaged microenvironment, such as peripheral, central, and spinal cord disinhibition, which greatly reduces clinical symptoms including spontaneous pain and hyperalgesia –91. The 2, O3 therapy is considered a promising conservative and mini-invasive intervention that can be used independently or in combination with other treatments to reduce neuropathic pain and improve pain function in patients affected by musculoskeletal disorders such as low back pain and knee osteoarthritis [Orthritis .Aptiva is an innovative non-drug option that uses a frequency rhythmic electrical modulation system (FREMS) to treat painful diabetic neuropathy. It uses modulated electrical pulses, which differ from those used in percutaneous electrical nerve stimulation (PENS), and it is intended to improve the supply of oxygen to nerve cells to reduce pain. However, current evidence regarding efficacy is limited due to the high costs of this type of therapy. Possibly because of underlying huge cost .A biopsychosocial approach used in several multidisciplinary pain management programs for reducing the severity of pain associated with diabetic peripheral neuropathy. CBT encourages patients to take control of their pain and lead a fulfilling life despite it . AddressThis includes nonconventional treatments such as acupuncture, meditation, massage, cupping, movement therapies, and relaxation techniques that may be used in conjunction with or in place of other medical treatments.β-endorphins and its effect on a somatotopic organization of the body represented in the auricle.A minimally invasive procedure using traditional Chinese therapy based on real experiences has proven beneficial and cost-effective in managing diabetic peripheral neuropathy, back pain, and shoulder pain , 97. ThiOne of the most widely used complementary therapies in clinical practices involves the use of essential oils extracted from plants that reduce neuropathic pain scores and improve the QoL, resulting in a positive impact on physical, emotional, and mental health . PreclinA good treatment strategy might take several trials of combining pharmacological and nonpharmacological therapeutic options. Pain management counseling and frequent communication is a must to target the right fit of regimes. The best outcomes have shown improvement over time with experimentation, much like a sliding scale for pain management.The most common adverse effects of various therapeutic options discussed above were constipation, nausea, drowsiness, and dizziness. An increase in the frequency of serious adverse events occurred with chronic treatment and polypharmacy.Precautions are warranted in patients with a history of substance abuse and other significant comorbidities like heart disease and dementia. A dosage adjustment is essential in renal failure or CYP450 enzyme-inhibitor interactions.Inadequate pharmacological response significantly contributes to drug non-compliance. In the context of neuropathic pain, minimal to no relief of pain can potentially lead to sleep disturbance, depression, fatigue, reduction in quality of life and driving ability.Many of the newer drugs that we mentioned in the study are in phase I and II. So, these drugs are not approved for use.We could not formulate new treatment modalities for the treatment of neuropathic painOur study does not include articles comparing superiority of combining pharmacological and nonpharmacological treatment modalities over pharmacological.Disease-specific treatment modalities are not clear.Limited articles on recent advances in psychological treatment modalities.The increasing prevalence of chronic neuropathic pain and its poor impact on the quality of life prompts the need for an early diagnosis and intervention. Recent advances in various pharmacological modalities have been primarily limited by the side effect profile of certain drugs and the cost incurred in making them available to the masses. Research addressing nonpharmacological measures might help to come up with cost-effective solutions with minimal side effects. A mixed approach consisting of symptomatic management during an acute episode and a simultaneous multidisciplinary approach for long-term pain management is thus warranted.


Interviews were transcribed verbatim and coded by two researchers using a thematic analysis approach. Stakeholders’ perceptions revealed a lack of awareness surrounding eligibility for assistance programs, a lack of knowledge regarding how to obtain resources and services, and stigma associated with receiving benefits. These remained significant barriers to obtaining healthful foods for households with young children before and during COVID-19. Nonetheless, barriers were exacerbated during the pandemic. Unemployment rates rose, intensifying these households’ financial hardships and food insecurity levels. Likewise, stakeholders suggested the need for families to become more aware of federal assistance eligibility requirements and available opportunities via social media and referrals. Identifying risk factors associated with food insecurity can inform future interventions to safeguard young children’s health and well-being.Children living in food-insecure households have poorer overall health than children in food-secure households. While U.S. nutrition assistance programs provide resources, these cannot consistently offer age-appropriate nutritional foods for young children. This study aimed to determine community stakeholders’ perceptions of the barriers and facilitators to obtaining adequate, high-quality, and age-appropriate foods for children ages 0–3 in Florida before and during COVID-19. Community stakeholders ( Food insecurity  affected 10.5 percent (13.8 million) of all U.S. households and 14.8 percent (5.6 million) of households with children under age 18 at some time during 2020  run out a formula in the middle of the month. And we are not able to get them until a week later, two weeks later, maybe the following month. So not having enough resources to meet the demand of the baby because that’s the only baby food we provide.” Nevertheless, participants stated that information provided to caregivers through nutrition education programs and the rapid changes in legislation to increase SNAP and WIC benefit utilization made it easier for caregivers to obtain these foods during this time.When asked about the services and resources available to address barriers to food security before COVID-19, community stakeholders mentioned several resources, including (1) information and referral services; (2) health promotion programs; (3) nutrition programs; (4) volunteer and intergenerational programs, and (5) housing programs. Information and referral services, as well as nutrition programs such as federally sponsored programs , food banks, food pantries, and community gardens, were the most mentioned among stakeholders.While participants mentioned most of the programs, services, and resources available before COVID-19 were still offered during the pandemic, they were economically impacted by COVID-19 response efforts . Community-based organizations faced dwindling resources despite the increased needs of individuals in communities. Nevertheless, stakeholders stated existing and new programs and organizations rapidly adapted and adopted new strategies to provide programming and resources to those in need, including virtual support and socially distanced measures. Volunteer and intergenerational programs and nutrition programs remained the most accessible resources to households with young children. This paper explored community stakeholders’ perceptions of the barriers and facilitators to food security in households with children under three before and during the COVID-19 pandemic. Exploring the perceptions of various stakeholders allowed for a better understanding of the factors contributing to food security in households with young children through diverse lenses, which allows for a more comprehensive picture of the ongoing challenges preventing these families from accessing adequate, high-quality, age-appropriate food for their children.While stakeholders suggested barriers to food security  remained the same during the COVID-19 response, new challenges emerged  due to possible virus exposure. Understanding the barriers that emerged during the COVID-19 pandemic highlights the challenges that often arise during times of crisis . It also encourages conversation and policy action toward future changes in social, economic, and environmental systems.Recent studies have found similar findings suggesting individuals consumed high rates of diets high in saturated fats, sugars, and refined carbohydrates, known to be contributors to obesity and type 2 diabetes ,51,52. MWhile previous research has also identified unemployment, a lack of transportation, and the inability to prioritize food purchasing  as contributing factors to food insecurity in adults, our findings provide insight into the unique barriers that families with young children face regardless of the impact of COVID-19 ,13,57. FFurthermore, despite shifts in emergency food assistance and federal nutrition assistance programs to increase food access and buffer against the loss of household income during the pandemic , stakehoCommunity stakeholders also expressed caregivers’ lack of knowledge and awareness about programs and resources addressing food security. As with previous research, findings from this study suggested this is due to the lack of community outreach opportunities and logistics associated with applying for and receiving federal, state, and local supplemental assistance ,60. MoreFurthermore, community stakeholders mentioned that individuals who lost employment yet whose household income was above the income eligibility threshold could not receive financial or food assistance benefits and support. The existing literature supports this finding, suggesting eligibility restrictions and enrollment barriers intensify the challenges for these households to access food and other resources ,64. OverWhile this study provides a unique insight into the barriers and opportunities related to food security in households with children under three, there are potential study limitations concerning the generality of the findings. First, study participants were part of a purposive sample of community stakeholders in one U.S. state . Thus, participants’ responses may not represent the perspectives of all types of stakeholders working with low-income families with children under three in Florida or beyond Florida. However, rigorous data collection techniques were utilized to diminish any potential bias. Additionally, given qualitative data were collected before, during the onset, and in the midst of the COVID-19 pandemic, participants’ responses may represent the political, economic, and social climate these communities were facing in response to the COVID-19 emergency response. It is important to note that depending on when the data were collected, participants may not have been able to recall all the barriers present or facilitators available before the COVID-19 pandemic. Likewise, given participants were sharing the barriers of individuals they served in their current positions, they may not have known all the barriers contributing to food security in this population, adding potential bias to the results. Furthermore, given that food insecurity affects all members of the household, it was challenging for stakeholders to identify barriers and facilitations impacting only children under the age of three. Thus, future research should explore the perceptions of caregivers of children under three years. Lastly, questions and probes utilized in this study could have potentially influenced the personal opinions, perspectives, and experiences of participants.Food insecurity is a public health issue affecting millions of households with children in the U.S.  The COVIThis paper explored community stakeholders’ perceptions of the barriers and facilitators to food insecurity experienced in households with children ages 0–3 in Florida before and during COVID-19. Stakeholders indicated that the families they work with identified stigma associated with applying for or receiving nutrition assistance benefits, a lack of knowledge on obtaining community resources and services, and a lack of transportation as barriers to food security prior to the COVID-19 pandemic. Further, stakeholders identified new challenges for families in accessing healthy and age-appropriate foods for their young children, including the fear of COVID-19 exposure when accessing food or benefits, and concern for higher unemployment rates and resulting negative impact on family income. Stakeholders also reflected on the opportunities available to these families to mitigate the barriers identified. They suggested both government and community organizations create innovative strategies  to maximize the opportunities available to these families to facilitate the access to and availability of nutritious and adequate foods for their young children.Despite existing policies and programs, significant gaps remain in achieving optimal food and nutrition security for families with children under three. Age-appropriate foods and additional resources are still needed and must be provided in non-stigmatized ways for food-insecure families with young children ages three and under, especially now in response to the COVID-19 pandemic. Food assistance policies and programs to achieve nutrition security should ensure optimal utilization by improving coordination across programs and providing equitable and non-stigmatized access to services and resources to improve access to healthy and affordable foods. Future research should assess existing policies and programmatic efforts to provide the equitable and stable availability, accessibility, affordability, and utilization of food with sufficient nutritional quality for young children.


To address the growing concern about loneliness and diminished well-being among persons with cognitive impairment, an intergenerational intervention based on reminiscence and digital storytelling was offered by trained college student volunteers to older adults living in the community. A randomized controlled trial was used to assess the effects of the intervention. Younger and older adult participants were randomly paired and assigned to reminiscence (n=20) or control  groups. Data were collected at baseline, mid-intervention, and at the end of the intervention. Friedman tests for non-normally distributed outcome variables and one-way repeated measures ANOVA for normally distributed outcome variables were conducted. Results showed that emotional loneliness, total social and emotional loneliness, quality of life, and positive affect significantly improved among older adults in the reminiscence group, especially between baseline and posttest. Results suggest that weekly intergenerational engagements with young adults benefit older adults with psychological well-being.


Patients with schizophrenia show severe difficulties in interpersonal communication, including impairments in conversation skills, like the turn-taking. To our knowledge, very few studies to date have taken into account conversation analysis in order to investigate turn-taking in schizophrenia patients.To investigate the conversational patterns in schizophrenia patients; to assess possible associations between dialogic features, abnormal subjective experiences and symptom dimensions.Thirty-six patients with Schizophrenia underwent an interview, subsequently analyzed with an innovative semi-automatic analysis. Positive and Negative Syndrome Scale (PANSS) was adopted for the investigation of psychopathology and Examination of Anomalous Self Experience (EASE) for Self-Disorders.Dialogic exchanges are graphically represented in Figure 1. An inverse correlation was found between participant speaking time and PANSS negative symptoms score , whereas no associations were found between conversational variables and PANSS positive or disorganization dimensions. Finally, a positive correlation was found between the EASE item “spazialization of thought” and average pause duration .The finding of a relationship between negative symptoms and conversational patterns suggest that conversational features in schizophrenia are expression of the “core” negative dimension of the disorder. The association with the phenomenon of thought spatialization seems to suggest that the disturbances of the stream of consciousness impact on natural dialogic interactions. Ultimately, conversation analysis seems a promising tool to study dialogic exchanges of patients with schizophrenia.No significant relationships.


Public health professionals, especially ones concerned with maternal and child health (MCH), need to engage in cross-sector collaborations to address social determinants of health. Health Impact Assessment (HIA) systematically brings public health perspectives into non-health decision-making contexts that influence social determinants. Alignment of MCH and HIA practice has not previously been documented.An exploratory review of HIAs conducted in the United States considered several dimensions of MCH-HIA alignment and produced data to test the hypothesis that HIAs involving MCH stakeholders are more likely to address MCH populations and relevant measures. The review examined three key variables for each HIA: inclusion of MCH-focused stakeholders, level of focus on MCH populations, and presence of MCH-relevant content.Of the 424 HIAs included in the database of US HIAs, 350 were included in this review. Twenty-four percent (84) included MCH-focused stakeholders, and 42% (148) focused on MCH populations. Ninety percent (317) included metrics or content relevant to at least one Title V National Performance Measure (NPM). HIAs that clearly included MCH stakeholders had seven times the odds of including both a focus on MCH populations and at least one NPM-relevant topic compared to HIAs that did not clearly include MCH stakeholders .Despite low engagement of MCH stakeholders in HIAs, many still consider MCH populations and measures. Intentional engagement of MCH workforce in HIAs could ensure greater alignment with existing MCH priorities  in a given jurisdiction. What is already known on this subject? Cross-sector collaboration has become increasingly important for public health practice. HIA is an effective tool for building collaborative relationships across sectors. The MCH workforce is in need of actionable frameworks for cross-sector collaboration to impact social determinants of health and equity.What this study adds? HIA practice in the US has not seen extensive involvement of the MCH workforce, but it has regularly incorporated MCH-relevant content. By filling this gap and becoming more involved in HIA, MCH professionals have an opportunity to build cross-sector capacity and ensure relevance of MCH content.Researchers, practitioners, and policy-makers need to address social determinants of health to meaningfully reduce population-level disparities and improve maternal and child health (MCH). Social determinants of health are conditions in the environments where people are born, live, learn, work, play, worship, and age that affect a wide range of health, functioning, and quality-of-life outcomes and risks .HiAP considers how to systematically integrate public health perspectives on social determinants and equity into decision-making across non-health sectors  to what extent have MCH-focused stakeholders been involved in HIA practice? (2) How often and to what extent do HIAs examine MCH subpopulations? (3) What proportion of HIAs include Title V National Performance Measures (NPMs) or closely related metrics in their analyses? (4) Are HIAs that engage MCH-focused stakeholders more likely to include information on MCH populations and NPM-relevant content? Fig.  to what The Health Impact Project, a collaboration of the Robert Wood Johnson Foundation and The Pew Charitable Trusts, hosts a web-based repository of information about HIAs conducted in the United States , decision-making level , and target sector . HIAs were excluded from the current analysis when project documentation was not available, either because the HIA was in progress or because available hyperlinks were no longer active and reviewers were unable to find publicly available documentation via web search based on HIA title and/or lead organization.involvement of MCH-focused stakeholders. MCH-focused stakeholders included organizations or individuals that focus on infants, children, youth, adolescents, mothers, pregnant individuals, and/or families. State or Local Health Departments were only included as MCH-focused stakeholders if available documentation clearly noted representation from an MCH-serving division, branch, or team . Reviewers did not assume inclusion of these perspectives unless stated. This variable was coded ‘yes’ if documentation revealed an explicit role for an MCH-focused partner in the conduct of the HIA, ranging from roles on the HIA project team or advisory committee to participation in document review or data collection as part of the process. If available documentation mentioned MCH-focused stakeholders but was unclear about the extent of involvement, reviewers coded this variable as ‘partial.’ The ‘partial’ designation was also used when the reviewer was unsure about the extent to which a given stakeholder explicitly focused on MCH, for example local educational institutions were regularly placed in this category.Researchers coded three primary variables for each HIA reviewed. First, they determined the attention given to MCH populations within the HIA. MCH populations include infants, children, youth, adolescents, mothers, pregnant individuals, and/or families. Reviewers coded this variable as ‘yes’ if documentation noted explicit focus on one or more of these MCH populations as part of the HIA scope. This meant that the HIA not only identified an MCH population as a subpopulation of concern, but that the assessment and/or recommendations reflect elevated attention on that group. Reviewers assigned a ‘partial’ designation if the HIA mentioned MCH populations but did not clearly incorporate them as part of the assessment. This included instances where a report includes statistics on an MCH population but not as a critical element of the analysis .The second variable considers inclusion of MCH content, reviewers determined whether each HIA included topics related to one or more of the Title V NPMs. These 15 measures were selected as the basis for defining "MCH content" in this review because national leaders have identified them as foundational to the work of public health MCH professionals, as measurable, as directly modifiable by states’ programmatic activities, and as meaningful when changed  of the 350 HIAs reviewed demonstrated clear inclusion of MCH stakeholders Fig. . In thatResearch Question 3: What proportion of HIAs include Title V National Performance Measures (NPMs) or closely related metrics in their analyses?Eighty-four percent of the 350 HIAs reviewed at least partially considered MCH populations according to publicly available materials. As illustrated in Fig. Eighty-nine percent of the 350 HIAs included information designated as closely related to or relevant for at least one NPM, and less than 2% included specific NPMs. The mean number of NPM-related topics included in an HIA was 2.62 (SD 1.80). The largest proportion of HIAs (30%) included two NPMs, and most (61%) included one to three topics  and ones with no clear inclusion of MCH stakeholders . The dependent variable was a combination of MCH population focus and inclusion of NPM-related topics, where an HIA had to satisfy both conditions to be coded as ‘yes’ .HIAs that clearly included MCH stakeholders had seven times the odds of including both a focus on MCH populations and at least one NPM-relevant topic compared to HIAs that did not clearly include MCH stakeholders . This association is statistically significant . Table To demonstrate the breadth of non-health policies informed by HIA, Table Nearly all HIAs reviewed (95%) considered an MCH population in some way or included information relevant to at least one NPM. In contrast, just over a third (36%) contained evidence of MCH stakeholder involvement. The current analysis demonstrates that MCH stakeholder involvement in an HIA is associated with greater odds of that HIA addressing MCH populations and relevant topics, suggesting an opportunity for MCH professionals and HIA practitioners to engage with one another in strategic efforts to inform decisions made outside the traditional public health sector. Aligning these efforts allows both MCH professionals and HIA practitioners to better advance a “Public Health 3.0” approach, wherein public health leaders partner across multiple sectors to address social, environmental, and economic conditions that affect health and health equity . This assignment of HIA responsibility to specific public health content areas might raise barriers to supporting active involvement of MCH professionals from within an agency, among other bureaucratic challenges. Without active attempts to bridge these intra-sector silos and address these challenges, HIA work done by one arm of a public health agency can easily occur in isolation from the other. As MCH leaders become more engaged in upstream policy work, awareness of opportunities to leverage existing cross-sector experience from within their own agencies is an asset. HIAs potentially present this type of opportunity, as do HiAP approaches more broadly (Rudolph et al., In terms of connecting to sectors outside of public health, Table Three interrelated limitations should be considered in interpreting these findings. First, approximately one in six HIAs listed in the Health Impact Project database did not have the publicly available documentation needed to be included in this analysis. Further, the database is populated mostly by voluntary self-reports from the HIA field, and thus, an unknown number of HIAs in the U.S. are not included in the data. How information from these HIAs might influence study results is unclear. Second, thoroughness of available HIA documentation varies widely (Rhodus et al.,  HIA is an established tool that supports prospective engagement by public health stakeholders in non-health decision-making contexts. This exploratory review indicates limited involvement of MCH-focused practitioners in HIA practice to date. The results reveal that despite this lack of engagement, a large portion of HIA practice considers populations and measures with clear relevance to MCH. When the MCH workforce is involved, HIAs are significantly more likely to include specific MCH content. Therefore, intentional alignment of MCH and HIA practice, along with capacity building to support use of HIA by MCH stakeholders, would potentially reinforce strategies seeking to inform decisions made in other sectors. As noted earlier, these decisions influence social determinants of health, the inequitable distribution of which underpin many health disparities. HIA is one method through which public health perspectives can be integrated into these influential decisions for population health. Limited involvement of MCH practitioners in HIA points to a missed opportunity to ensure that their particular perspectives on public health are actionably included in these cross-sector collaborations to address social determinants.


Overview of impact of sequencing technologies and its applications in livestock research. Canis lupus familiaris), sheep (Ovis aries), pigs (Sus scrofa), horses , chicken , and ducks (Anatidae) as well as how it can improve the monitoring and detection of zoonotic infections. We also described several high-throughput sequencing approaches for improved detection of known, unknown, and emerging infectious agents, resulting in better infectious disease diagnosis, as well as surveillance of zoonotic infectious diseases. In the coming years, the continued advancement of sequencing technologies will improve livestock research and hasten the development of various new genomic and technological studies on farm animals.Increasing globalization, agricultural intensification, urbanization, and climatic changes have resulted in a significant recent increase in emerging infectious zoonotic diseases. Zoonotic diseases are becoming more common, so innovative, effective, and integrative research is required to better understand their transmission, ecological implications, and dynamics at wildlife-human interfaces. High-throughput sequencing (HTS) methodologies have enormous potential for unraveling these contingencies and improving our understanding, but they are only now beginning to be realized in livestock research. This study investigates the current state of use of sequencing technologies in the detection of livestock pathogens such as bovine, dogs ( The amount of DNA sequence data that can now be produced using next-generation sequencing (NGS) platforms  is a clear example of this step-change. Similarly, recent advances in protein and peptide separation efficiencies, as well as highly accurate mass spectrometry, have facilitated protein identification and quantification in a given sample. These biotechnology advances are increasingly being applied to the study of animal infectious diseases, and they are beginning to revolutionize the way biological and evolutionary processes can be studied at the molecular level.Emerging infectious diseases have significantly risen in recent years owing to rising globalization, intensifying agriculture, urbanization, and climatic changes. Over the last few decades, emerging infectious diseases, such as avian influenza, African swine fever, foot and mouth disease, and bovine spongiform encephalopathy, have been associated with domestic and companion animals, and have caused major losses to livestock rearing communities, in addition to posing significant threats to human and animal health To address diverse diagnostic issues, such as the genetic relationships between bacteria or viruses related to livestock or companion animals, the detection of mutations in viral or bacterial genomes that lead to resistance against antivirals or antibiotics, numerous companies are developing relatively affordable, rapid, and smaller devices based on advanced technologies for the rapid detection of infections in domestic animals The second and third-generation sequencing platforms provide numerous benefits over traditional microbiological diagnostic techniques, including the ability to detect fastidious or non-culturable pathogens and co-infections. The HTS enables researchers to simultaneously identify a wide range of DNA sequences, either using a specific genetic region (metabarcoding/amplicon-based methods) or all genetic material. Moreover, sequencing technologies have been used to characterize viral diversity in humans and animals. From epidemiology to the evolution of viral quasispecies to metagenomic characterization of unknown pathogens or microbial communities, molecular identification has significant implications.Canis lupus familiaris, Ovis aries, pigs, horses, chickens, and ducks). Further prospective aspects of HTS are also discussed, with a focus on improving monitoring and detection of zoonotic infections, as well as diagnosis and control of infectious zoonotic diseases.Since the field has rapidly developed owing to continuous improvement and refinement of existing systems as well as the release of completely new platforms, resulting in a dramatic reduction in DNA sequencing costs, making the technology more accessible to the average laboratory. In this article, we attempted to summarize the use of sequencing simulations (HTS) in veterinary research, i.e., an in-depth discussion on HTS-based technologies in the detection of livestock pathogens -based methods were used for large-scale diagnosis and rapid identification of avian influenza-specific genomes. qRT-PCR (quantitative reverse transcription polymerase chain reaction) is a single-tube closed technique that can be used in veterinary medicine. Portable adaptations for use in the field may allow for rapid decision-making during an emergency outbreak.The sequencing technology, which was initially developed for mapping genes, has been predominantly applied to develop or improve therapeutics to detect a wide variety of veterinary pathogens 3Zoonosis is a disease or infection that can be transmitted from animals to humans Depending on the mechanisms of transmission and epidemiology, zoonoses can be classified into the following four major types: cyclozoonoses , metazoonoses , saprozoonoses , and direct zoonoses . Further, zoonotic diseases may be classified based on the route of transmission, pathogen type, and degree of contagious mcr-1 in three E. coli strains isolated from retail chicken meat  in humans are caused by the spillover (cross-species spillover) of pathogens from animals, and locations where individuals and animals frequently interact are potential spillover sites Bos taurus), pigs (Sus scrofa), sheep (Ovis aries), goats (Capra hircus), chicken , and ducks (Anatidae) are associated with primary agricultural production.Overall, the outbreaks of highly pathogenic diseases have mainly originated in the livestock industry and some of them have caused huge losses 4The etiological agents may infect the host, and in advanced phases, these pathogenic agents cause worldwide epidemiology through re-transmission and amplification in varied livestock populations, as well as new zoonoses. This can result in the emergence of novel strains or species that are more virulent and/or resistant to antibiotics. Priority is given to the use of current technologies such as the HTS system and molecular epidemiological techniques  for active and broad zoonoses surveillance and monitoring, ensuring the formation of an adequate response team within a unified health-based framework .Fig. 2ScBioinformatics, the area of study which focuses on methodologies for retrieving, interpreting, and archiving biological information, is an integral part of all HTS applications The continued development of HTS techniques enhances the chances of detecting low copy-number pathogens by allowing deeper sequencing to be performed faster and cheaper. Importantly, sampling, sample preparation, and enrichment methods have all been shown to have a significant impact on the result of HTS-based diagnostics and thus should be considered as integral stages. Because proper diagnostic specimen sampling is critical for all investigations of animal disease. The majority of sample preparation and enrichment techniques are made up of numerous distinct processes, including homogenization, filtration, ultracentrifugation, and nuclease treatment, as well as nucleic acid extraction and purification followed by amplification. The viral genomic sequences (directly as DNA or reverse-transcribed RNA) in the samples must be translated into sequencing libraries appropriate for future cluster creation and sequencing in most existing HTS systems. The different sequencing methodologies of the major commercial HTS systems are now available. Their application areas include running time and sequence data output .Table 3C5High-throughput sequencing has the potential not only to uncover novel pathogens and provide a thorough image of the virome but also to contribute to a better understanding of host responses to varied viral infections, leading to a better understanding of infection pathophysiology. The Illumina Digital Gene Expression system, which leverages Illumina deep-sequencing technology (both short and long read from HiSeq and MiSeq), was used to investigate the host response to the PRRS virus. This proved to be a strong strategy since it confirmed many of the previously known traits and expression patterns while also uncovering multiple different ones. Thus, when applied to analyses of changed gene expression in viral illness, HTS might give a better knowledge of pathophysiology, help in the development of antiviral medicines, and aid in the identification of genetic markers for resistance Although convenient, molecular identification methods have their limitations. False-negative findings can occur with any PCR test in case of pathogen loads below the detection limit or the presence of PCR inhibitors, affecting the utility of PCR for a broad spectrum of pathogen detection Fetal bacteria and viruses differ widely, and the primary goal of viral identification is to link them to illness. NGS technologies are becoming an essential tool for detecting known viruses and identifying new viruses in clinical and environmental samples 5.1Staphylococcus aureus, etc.) or environmental pathogens like animal dung, soil, etc.Mastitis, a bovine disease caused by inflammation of the mammary gland, is the most economically significant illness in dairy cattle. Several microbes have been identified as the source of this disease, and managing mastitis is becoming difficult Environmental pathogens are now widely recognized as the primary cause of clinical mastitis. To define clinical mastitis in cows on large dairy herds in Wisconsin, 50 herds were evaluated. Microbiological studies have been conducted to describe mastitis pathogens and have revealed that gram-negative bacteria are the most common cause of clinical mastitis Our understanding of bovine respiratory health is constantly evolving in response to technological developments. Many techniques, such as serology, microbial culture, and PCR, have been utilized for pathogen detection in cattle. Today, NGS appears promising, and due to the democratization of technology, NGS technologies (HiSeq and MiSeq) are now becoming more widely available. NGS is beneficial in that all pathogens may be discovered simultaneously, without having to prioritize the detection of a pathogen Pasteurellaceae, Leptotrichiaceae, Mycoplasma, and Fusobacterium are the most abundant bacteria in the lungs and lymph nodes of BRD-dead calves As discovered by NGS, 5.2Canine vector-borne diseases are a collection of infectious disorders spread by arthropod vectors, such as ticks and other pathogens, such as bacteria and protozoa Anaplasma platys, and Ehrlichia canis, commonly cause canine cyclic thrombocytopenia and canine monocytic ehrlichiosis Dog bites can cause severe tissue damage as well as the transmission of bacterial infections and rabies. Rabies is a well-known zoonotic illness that has been around for approximately 4,300 years. It is a global zoonosis caused by a lyssavirus, with several host species, primarily dogs, acting as reservoirs for infection Anaplasma platys, Babesia gibsoni, Babesia vogeli, Ehrlichia canis, Hepatozoon canis, and hemotropic Mycoplasma spp. are all endemic in the Asia-Pacific region and can be detected using qPCR. The combination of qPCR with NGS technology provides a valuable high-throughput diagnostic tool for epidemiologists, researchers, and clinicians Bocaparvovirus genus and have been associated with respiratory and gastrointestinal diseases in both humans and animals. CBoV-2 has also been discovered in NGS data of lung samples and confirmed through traditional PCR experiments Vector-borne pathogens Haemoparasites cause some of the most common and debilitating diseases in dogs in the world and pose a considerable zoonotic threat to humans. The sequence-metabarcoding-based technique has been used to test a variety of blood-borne apicomplexan and kinetoplastid parasites in Bangkok and Thailand's temple dogs, demonstrating how NGS techniques can cover atypical infections 5.3Pasteurella spp. is the most common etiological agent linked with pneumonia in lambs, while Escherichia coli is in non-parasitic scours. Pneumonia is also the most common cause of death in ewes, and although Pasteurella spp. appear to be the most common etiological agents, agents vary with location Pneumonia and scours are the leading causes of death in lambs. Internal parasites, sheep scabs, and footrots have been identified as significant diseases in sheep by the Moredun Foundation (1997). Lambs are constantly challenged by gastrointestinal parasites, which are only temporarily inhibited by anthelmintic treatment. Gastrointestinal nematodes are one of the most common parasites found in domestic sheep worldwide. To detect CNV associated with disease, researchers have used data from NGS. CNV is a variation that contributes to genetic diversity and disease features. However, CNVs in sheep are understudied compared to those in other domestic animals Along with G.I. nematodes, multiple co-infecting trichostrongylid nematode species, each with a different incidence of benzimidazole resistance, make sheep an excellent host system. Deep amplicon sequencing has been developed and validated as a powerful method for detecting and quantifying the frequency of SNPs linked to benzimidazole resistance. It is a new approach for identifying anthelmintic resistance mutations in parasitic worm populations in both animals and humans Mycoplasma agalactiae is a dangerous pathogen of small ruminants that spreads mainly through the mammary system, causing acute to subacute mastitis that progresses to a chronic, difficult-to-cure illness. Mycoplasma agalactiae is a species of bacteria in the genus Mycoplasma are the smallest bacterial cells so far discovered that lack a cell wall around their cell membrane M. agalactiae type strain PG2. It was the first study to look at the host transcriptomics of M. agalactiae infection and the corresponding immune-inflammatory responses 5.4Klebsiella pneumoniae is a common harmless bacterium of the intestines, but its migration into the other parts of the body turns it into a superbug that is practically impossible to fight with widespread antibiotics Klebsiella pneumoniae strains isolated from hospitals in Israel K. pneumoniae strains were isolated from swine farm in Malaysia K. pneumoniae isolate from swine in China have been characterized Erysipelothrix rhusiopathiae, a strain isolated from swine, through the identification of novel chimeric integrative and conjugative elements responsible for drug resistance Aeromonas salmonicida aquatic pathogen and establish a link with swine pathogen to transfer antibiotic resistance gene E. coli, as well as resistance genes carrying two novels Proteus genomic island 2 (PGI2) variants in Proteus mirabilis were studied using the PacBio platform Streptococcus suisTet(63) novel tetracycline resistance gene from Staphylococcus aureus was identified through the genome sequencing platforms Illumina HiSeq and Oxford Nanopore The PacBio method is suited for de novo assembly and base modification detection 5.5+ release on ion semiconductor sequencing chips during the binding of new nucleotide in the strand by DNA polymerase and generates read lengths of around 200 bp lies in between short and long read length NGS technologies E. coli (APEC) infection, as well as the integrated expression of miRNAs and mRNAs in the lungs of AIV-infected broilers. In the APEC investigation, potential genes for host response were discovered inside critical physiological pathways such as the T-cell receptor (TCR) signalling pathway.Influenza A virus sequencing costs were reduced by 92 % from 2010 to 2015 due to new technologies Campylobacter jejuni, Listeria monocytogenes, and Salmonella enterica, via different NGS platforms, has suggested that integrated data analysis based on Illumina and Ion Torrent is a more suitable method The whole-genome sequencing of the most common foodborne disease-causing bacteria, such as 5.6Illumina Genome Analyzer IIx was used to analyze the viral heterogeneity of rabies genomes in infected tissues, which allowed for extensive and comprehensive genome sequencing of the EEE virus 6Pathogen infections in wild and domestic animals pose a global health risk concerning sporadic human zoonotic infections. Recognized zoonoses have increased to over 200 due to ecological, climatic, and sociocultural changes. Zoonoses can be categorized into emerging, reemerging, and neglected classes of diseases 6.1The Global Health Security Agenda (GHSA) was launched in 2014 to monitor and help prevent zoonotic diseases for global health security Buffalopox or pox-like illnesses have been observed in buffaloes, cows, and humans in many parts of the world. Since its initial outbreak in India, many epidemics have followed. Buffalopox virus, the primary agent of the disease, belongs to the genus Orthopoxvirus. Disease control is challenging in nations where the disease is prevalent, and animal migration is difficult to manage Mycobacterium chimaera (M. chimaera), a nontuberculous mycobacterium that belongs to the Mycobacterium avium complex, is an opportunistic and ubiquitous human pathogen found especially in water sources. Patients exposed to contaminated heater-cooler equipment used during heart surgery contracted M. chimaera infections. M. chimaera infection can be diagnosed using a plasma-based NGS test Whole-genome sequence analysis of the SARS-CoV-2 virus revealed that it shares an identity with a horseshoe bat coronavirus (96.2 %) and SARS-related coronaviruses (79.6 %) 6.2Because of its inherent benefits as a screening and characterization technique, HTS is suited for application in poultry vaccine innovation and quality control An intriguing use is the investigation of interactions between emerging field strains and vaccination strains. Recent research on infectious ILTV showed that separate recombination processes between different attenuated vaccination strains caused virulent recombinant viruses which became the dominant strains responsible for widespread illness in commercial Australian chicken flocks Using HTS, the researcher can now obtain an insight into the mechanisms that result in attenuating mutations throughout the serial passage of a virulent strain. Although the above examples are for bird vaccines, it should be noted that comparable HTS procedures may be used for vaccines used in many other animal species, even humans.7NGS technologies have completely transformed the field of genomics. Nevertheless, there are several significant limitations to HTS-based pathogen inferences. In environmental samples, the metagenomic process tends to compound errors, obscuring inferences about pathogen diversity. Because pathogens and parasites are so diverse, developing primers to target numerous pathogens for metabarcoding is difficult. Furthermore, pathogen database coverage is significantly lower than in other organisms, resulting in identification uncertainty and inaccurate estimates of pathogen richness. Nevertheless, costs are still high, particularly in areas with the greatest diversity of pathogens and those most likely to have an adverse effect on both human and animal health. Determining pathogen virulence in humans or their domestic animals is also a crucial challenge. Although it is still difficult to predict when an outbreak of infectious disease will occur, HTS methods have significant benefits for enhancing urgently required surveillance and expanding our knowledge of infectious diseases.This work was supported by the National Research Foundation of Korea grant funded by the Korean government (2020R1A2C2004128) and the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (2019R1A6A1A10072987). The authors are thankful to the Brain Pool Program supported by the Ministry of Science and ICT through the National Research Foundation of Korea (2022H1D3A2A02053110).Godagama Gamaarachchige Dinesh Suminda: Conceptualization, Data curation, Writing – original draft. Srishti Bhandari: Conceptualization, Data curation, Writing – original draft. Yoonkyung Won: Resources, Data curation. Umesh Goutam: Writing – review & editing. Krishna Kanth Pulicherla: Formal analysis, Investigation, Validation. Young-Ok Son: Formal analysis, Investigation, Supervision, Writing – review & editing. Mrinmoy Ghosh: Conceptualization, Writing – review & editing.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Summary: DMM is launching a new Subject Focus on genetic variance in human disease. Here, we discuss this ongoing series of invited articles and reflect on advances in understanding the genotype–phenotype complexities in disease. Genetic variance in human disease: decoding diversity to advance modern medicine’, spearheaded by Associate Editor Monkol Lek and Editor-in-Chief Liz Patton. This ongoing series of invited articles reflects on the latest advances in our understanding of genetic variance and genotype–phenotype complexities in disease. New Interview, Perspective and Review articles will discuss model systems and tools, as well as striking examples of how combining human genomic data with experimental systems helps us understand the broad spectrum of disease presentation, assess risk and identify treatment opportunities.2021 marked the 20th anniversary of the publication of the draft human reference genome. Since then, many technological advances have been made, and the wealth of human genomic and transcriptomic data has been expanded, deepened and diversified . 2022 wain silico, in vitro or in vivo. Advances in multi-omics and imaging alongside improved integration across model systems allows thorough examination of disease phenotypes and the degree to which genetic variance affects them. Furthermore, rapid screening and in-depth phenotyping of potential disease-causing variants in organisms such as Drosophila  significance , which posophila , zebrafiosophila , Caenorh elegans  and yeas elegans  facilita elegans . Similaredictors . Furtheredictors . To effeedictors .ALDH2 variant. This single variant has been linked to a multitude of phenotypes, yet there is still more to explore beyond its alcohol-related effects (In rare and ultra-rare disease, low numbers of patients can make it difficult to pinpoint a genetic diagnosis and even harder to develop effective treatments. A solution to this urgent issue is enhancing global collaboration and data sharing, enabled via platforms such as the Matchmaker Exchange , helping effects . WhetherAnother area of difficulty is the exploration of diseases with complex genetic aetiology. Advances in computational models that assess polygenic risk scores are necessary to carefully evaluate disease susceptibility . Hand inGenetic variance in human disease: decoding diversity to advance modern medicine’ will continue to highlight how researchers are fine-tuning genotypic and phenotypic data to infer disease biology, risk and therapy. Technological advances have proven vital to build rich datasets, but studies also need to consider genetic variation between populations to mitigate health disparities. As modern medicine embraces genomics, global collaborations and knowledge sharing should be a priority. By curating an ongoing series of invited articles that examine these nuanced and complex issues, we hope to support the community in building an inclusive future for translational genomic medicine.DMM's new Subject Focus ‘


Apathy is a common condition that involves diminished initiative, diminished interest and diminished emotional expression or responsiveness. It is highly prevalent in the context of a variety of neuropsychiatric disorders and is related to poor health outcomes. Presence of apathy is associated with cognitive and functional decline in dementia. Despite its negative impact on health, there is no definitive treatment for apathy, a clinical reality that may be due in part to lack of knowledge about assessment, neuropsychological features and neurobiological underpinnings. Here, we review and synthesize evidence from clinical, epidemiological, neuropsychological, peripheral biomarker and neuroimaging research. Apathy is a common feature of depression and cognitive disorders and is associated with impairment in executive function. Neuropsychological and neuroimaging studies point to dysfunction of brain circuitry involving the prefrontal cortex, especially the dorsolateral prefrontal cortex circuit, the dorsomedial prefrontal cortex circuit, and the ventromedial prefrontal cortex circuit. However, inconsistent findings, particularly in neuroimaging may be due to heterogeneity of apathy symptoms (with a need to better elucidate subtypes), neuropsychiatric comorbidities, the severity of cognitive impairment and other factors. These factors need to be accounted for in future studies so that biomarker research can make progress. On the whole, the literature on apathy has identified likely neurocognitive, peripheral biomarker and neuroimaging targets for understanding apathy, but also points to the need to address methodological issues that will better inform future studies. In turn, as we learn more about the underpinning of apathy and its subtypes, subsequent research can focus on new neurally based interventions that will strengthen the clinical management of apathy in the context of its comorbidities. Most clinicians caring for older adults recognize that apathy is common in late life, particularly among individuals with depression and dementia. Presence of apathy affects psychiatric and neurological outcomes , 2, takeIn this paper, we provide an updated review of the literature on apathy, with a particular focus on its role in depression and neurocognitive impairment, both major (dementia) and minor (syndromes related to mild cognitive impairment). While our goal is to provide a clinical neuroscience-based overview of neurobiological and neuropsychological phenomena related to apathy, we feel it is important to start with a clinical perspective. Given the outstanding questions about presentation of apathy, its characterization and assessment, its impact on a variety of medical and psychiatric conditions, and its treatment, beginning with a review of clinical issues surrounding apathy should provide a strong foundation from which to build a clinical neuroscience understanding of its neurobiological and neurobehavioral basis.Apathy is a common and pervasive neuropsychiatric syndrome . It was Prior studies have shown that the prevalence of apathy in mild cognitive impairment (MCI) ranges between 10.7% and 44.8% . Apathy Whether considered a symptom or a standalone disorder, apathy has been the subject of much debate. Across the literature, many terms have been used to describe similar presentations to apathy: amotivation, avolition, abulia, withdrawal, social isolation, etc. To delineate a symptomatic apathy syndrome, consensus statements have been issued by expert groups and are detailed in Tables To reliably assess apathy and track therapeutic interventions, use of validated scales is generally recommended, especially the Apathy Evaluation Scale and the Dementia Apathy Interview and Rating. The Apathy Evaluation Scale (AES)  measuresOther promising avenues look to technology to gather data that can supplement and inform clinical information such as passive environmental sensing technology.There are no established clinical guidelines for treatment of apathy . With reThere are no FDA-approved medications for apathy. The utility of selective serotonin reuptake inhibitors (SSRIs) for apathy in depression is unclear. The literature on the topic includes several case reports that described onset or worsening of apathy with SSRIs in depression . In one For treatment studies of apathy in AD, we consider the ADMET trial. In this six-week, randomized, phase II, double-blind, placebo-controlled multicenter trial enrolling Alzheimer’s disease participants with apathy assigned to methylphenidate 20 mg daily or placebo, there was a statistically significant reduction in CGI-C and Neuropsychiatric Inventory apathy scores with active treatment, but there was no treatment difference on the AES . A PhaseRepetitive transcranial magnetic stimulation (rTMS) was shown to improve AES-C scores significantly compared with sham treatment in a randomized, double-blind, parallel-arm, sham-controlled pilot study in subjects presenting with apathy in AD. The authors proposed several mechanisms for this finding, including an enhanced dopamine transmission, increased neuronal activity in prefrontal regions, and neurotrophic/neuroprotective effects when the DLPFC  is stimulated. This effect was significant at four weeks but not maintained at 8- or 12-week follow-up, possibly due to a small sample of 20 participants and short duration of treatment .The core definition of the apathy syndrome is a reduction in motivated goal-directed behavior. Engaging in motivated behavior requires a cost-benefit evaluation of whether the reward associated with that potential behavior outweighs the cost of performance . MotivatThree frontostriatal circuits underlie executive functioning and motivational states. These circuits include the dorsolateral prefrontal cortex (DLPFC) circuit, the dorsomedial prefrontal cortex (DMPFC), and the ventromedial prefrontal cortex (VMPFC) circuit. All three circuits originate in the prefrontal cortex and have direct and indirect pathways that project to the striatum, then to the globus pallidus and substantia nigra, and onto to the thalamus before looping back to the prefrontal cortex . The thr2/3) receptor availability in the nucleus accumbens is negatively correlated with apathy measured with the AES in depressed adults [The DLPFC circuit is closely associated with the core executive functions of working memory, response inhibition, and mental flexibility which are foundational processes for sustained attention, planning, and problem solving . Clinicad adults .The DMPFC circuit originates in the anterior cingulate cortex (ACC), a prominent hub of both cognitive and reward/emotional processing. The ACC influences behavior through the initiation and monitoring of action – guiding attention in response to changes in motivation and incentive . StructuThe vmPFC circuit originates in the lateral orbital gyrus of Brodmann’s area 11 and the medial inferior frontal gyrus of the areas 10 and 47 . Damage VMPFC circuitry is also engaged by effort or reward-based decision-making tasks – such as the Effort Expenditure for Rewards Task (EEfRT) and Iowa Gambling Task (IGT). During the IGT participants choose cards from one of four decks with the goal to win as much money as possible . SelectiApathy and executive dysfunction commonly travel together in older adults. For example, an early study by McPherson et al. found that AD patients with apathy performed significantly worse compared with AD patients without apathy on several measures of executive functioning including response inhibition, cognitive flexibility, and sustained attention . Yet, itIncreases in the prevalence of apathy coincide with increases in dementia severity and frontostriatal degeneration in neurodegenerative diseases such as AD, Parkinson’s disease, FTD and Huntington’s disease. For example, the estimated prevalence of apathy is 18% in MCI or very mild AD patients and 39 and 48% in mild and moderate AD patients   study . Effortsn = 22,760 and Alzheimer’s Disease Neuroimaging Initiative, ADNI, n = 1733), lower Aβ42 was associated with a steep increase in apathy, while higher tau was associated with a marked decrease in apathy over a five-year period [Across a variety of neurological and neuropsychiatric conditions, there is a growing literature on peripheral biomarkers related to presence and severity of apathy. In particular, there appear to be links between apathy and inflammatory markers. Among AD patients, compared with those without apathy, those with apathy had higher levels of interleukin-6, interleukin-10, and leptin . In a str period . Among ar period . In a prr period .There are also negative studies in this area. In the Leiden Study of adults 85 years and older, no association at baseline was found between C-reactive protein (CRP) concentration and apathy or depression . In subjAs indicated in the prior section, and consistent with prior reviews on the topic, apathy has largely been attributed to structural and functional changes in the frontostriatal circuitry, particularly the ACC, OFC, ventral striatum, and insula. From a network perspective then, apathy has most often been tied to dysfunction in reward and salience networks, although increasing evidence suggests an additional role for the Executive Control Network  in the etiology of apathy –76. HoweNeuroimaging studies on the neural correlates of apathy in AD have covered a wide range of neuroimaging techniques including T1 structural magnetic resonance imaging (sMRI) for brain structural volume and/or cortical thickness, T2 fluid-attenuated inversion recovery (FLAIR) for white matter lesions/hyperintensities (WML/WMH), diffusion tensor imaging  for measures of fractional anisotropy (FA), mean diffusivity (MD) or tractography, fluorodeoxyglucose-positron emission tomography (FDG-PET) for metabolism or perfusion, Pittsburgh compound B (PiB)-PET for Aβ deposition, (11)C-PBB3-PET for tau imaging, SPECT for blood flow and resting-state fMRI (rsfMRI) and task-related fMRI (tfMRI). As demonstrated in Table n = 10) and low (n = 7) Apathy Scale scores. They also acquired T1-weighted imaging to measure regional cortical thickness and diffusion tensor imaging to measure FA for white matter integrity. They investigated the association among focal Aβ and tau deposits, neural loss of focal brain, disruption of connected fibers and the severity of apathy. While they did not find significant differences in Aβ deposition between AD patients with high vs. low apathy scores, they did find an association between apathy and elevated tau deposition in OFC, decreased OFC cortical thickness, and decreased fractional anisotropy (FA) in the uncinate fasciculus, which connects to the OFC. Further path analysis indicated that the increased tau accumulation in OFC could affect apathy directly and through the reduction of OFC thickness and subsequent decrease of FA in uncinate fasciculus. This is one of the very few studies that has taken advantage of multi-modality neuroimaging data and pursued the causal relationship among findings from multi-modality imaging data. However, studies on PET often suffer from a small sample size. Even without PET imaging to confirm the pathology, more studies using multi-modality neuroimaging are still needed to better understand the disrupted brain regions or neural networks related to apathy.In addition to 11C-PBB3 PET scans for tau deposits, Kitamura and colleagues  also conEmotional apathy , which is characterized by emotional blunting and reduced empathy, is related to the disruption of the orbito-medial stream . Executive apathy  is characterized by difficulties in planning and organizing goals for the future and is related to the disruption of the dorsolateral stream . Initiation apathy , characterized by indolence or lack of initiation, is related to deficits in the basal ganglia, the dmPFC, the premotor medial PFC, and ventral ACC. Inconsistency in these reported imaging results may be due in part to variability of different apathy subdomains across studies. The majority of studies on apathy used the Neuropsychiatric Inventory (NPI), which does not have multidimensional constructs for studying the subdomain-associated neural mechanisms.Apathy is not a unitary construct. Levy and Dubois proposed three subtypes: emotional-affective, cognitive, and auto-activation apathy  to form n = 19) and “without lack of initiative and interest” (n = 12) [Only a few studies examined subdomain-related neural substrates , 82. Ben(n = 12) , 84 that(n = 12) . It is iAnother SMRI study examined gray-matter intensity in AD and behavioral-variant frontotemporal dementia (bvFTD) . RegardlApathy commonly occurs in neurodegenerative disorders such as Parkinson’s disease (PD), AD, frontotemporal dementia (FTD), and Huntington’s disease (HD). A natural area of inquiry is whether apathy of these neurodegeneration disorders involves the same neural circuits and to what extent there is overlap in brain circuitry across disorders. Based on the limited number of existing studies that have sought to address this question, the presence of apathy associated with each neurodegenerative disorder appears to be linked to more predominant neural changes. Go and colleagues compared apathy and brain atrophy between frontotemporal dementia  and AD (n = 18) patients . They usSimilar to comparisons on neural substrates of apathy among neurodegenerative diseases, there are very few studies compared the similarity and differences in neural mechanisms of apathy between AD and late-life depression. Although there are no studies that directly compared apathy-related neuroimaging features between AD and late-life depression (LLD), one systematic review  comparedn = 79), with apathy (n = 66), or with both depression and apathy (n = 33) [Apathy and depression also have overlapping components. Depression is often associated with dysfunction in the SN and reward-related network, so it follows that studies are needed that directly compare depression- and apathy-associated neural network function. A few studies directly compared the neural correlates between depression and apathy , 90. Onon = 651) found that focal grey matter atrophy and WMH burden were associated with worsening neuropsychiatric symptoms (NPS) including apathy over time in MCI and AD, with WMH having the greater contribution to NPS [Another understudied issue related to apathy in AD is whether apathy is due to AD pathology or due to microvascular structural damages and cerebrovascular disease. Studies using T2 FLAIR to examine white matter lesions (WML) or white matter hyperintensities (WMH) have partly addressed this question –94. One n to NPS . Increasn to NPS –90 are gMany neuroimaging studies have used small sample sizes and did not control for general levels of disease severity. This holds true particularly for PET and SPECT studies but was also the case for early sMRI studies as well. In these small-sample studies, one should be concerned about embracing any notions of causality. In addition, prespecified region-of-interest (ROI) analyses often predominate rather than atheoretical whole-brain studies. One caution with such “hypothesis-driven” approaches is creation of a bias in the literature that could lead to the perception of a well-established consistent association between apathy and one or more specific regions. More multi-modality studies using state-of-art data analyses methods will reduce this hypotheses-driven induced bias in the literature.Apathy is a common and complex condition that clinically occurs alone but more frequently in the context of a variety of neuropsychiatric disorders. It is often found accompanied by executive dysfunction. While there are no FDA-approved pharmacological treatments for apathy, there is a mixed literature with some support for use of methylphenidate, SSRIs and cholinesterase inhibitors for apathy when it occurs in certain conditions. Repetitive TMS may hold promise as a treatment. The underlying pathophysiology is linked to pro-inflammatory processes that affect key regions of the brain, especially the frontostriatal circuits. Neuroimaging studies have helped identify possible biomarkers of apathy, but inconsistent findings may result from heterogeneity of expression of apathy , presence of comorbid neuropsychiatric disorders in which apathy is common, a spectrum of severity of cognitive function, and a variety of sociodemographic factors.Future research should focus on identifying underlying processes and brain circuitry related to apathy across a variety of conditions, especially in depression and Alzheimer’s disease and related dementias. Such studies will help elucidate the heterogeneity of apathy and point to more tailored treatments. As potential candidate interventions are identified, subsequent clinical trials will need to account for confounding factors such as mood and cognition, and the presence of psychomotor slowing or parkinsonism .


COG4 gene. Magnetic resonance imaging revealed a critical stenosis of the cranio-cervical junction (CCJ) which required surgical treatment to attempt sufficient neurological decompression. The patient underwent decompression of CCJ under general anesthesia. There was no significant radiological and clinical improvement during the postoperative period. Conclusions: SWS is presented as an extremely rare congenital disease in children. The clinical condition of our patient confined surgical possibilities, therefore further treatment in such patients should be appropriately evaluated.Introduction: Saul Wilson syndrome (SWS) is a rare congenital syndrome characterized by a variety of symptoms, mostly skeletal changes. Saul and Wilson were the first to describe children with extremely short stature and craniofacial dysmorphism. Case report: We present a case of a 15-years-old boy with clinical and radiological characteristics of SWS. Genetic examination identified a pathogenic heterozygous variant in the  COG4 (606976) gene on chromosome 16q22, and represents a rare genetic autosomal dominant disorder typically caused by a de novo pathogenic variant. SWS is a skeletal dysplasia characterized by numerous skeletal disorders, such as profound short stature, clubfoot and short distal phalanges of fingers and toes. Besides skeletal features, patients usually have characteristic craniofacial features such as prominent forehead, prominent eyes and micrognathia, ocular disorders and hearing loss. Early development is usually delayed with normal cognition. The diagnosis of SWS is established in a proband with marked short stature, typical facial and skeletal features, and a heterozygous pathogenic variant in COG4 identified by molecular genetic testing [Saul-Wilson syndrome (SWS) OMIM#618150) is caused by recurrent de novo heterozygous missense mutations in the conserved oligomeric Golgi—8150 is cCOG4 gene result in altered proteins in the COG complex and change retrograde transport of proteins, which consequently results as SWS [COG4 variants have been reported; both resulted in a p.Gly516Arg missense change [COG4 is a subunit of the COG complex and an important intermediary in transport of proteins between the Golgi apparatus to the endoplasmic reticulum. Mutations of the s as SWS . To dateThe authors present a rare case of a boy suffering from SWS complicated with critical stenosis of cranio-cervical junction (CCJ) and atlanto-axial dislocation.A 15-year-old boy suffering from SWS was born from the third pregnancy of nonconsaguine young and healthy parents as a hypotrophic infant with a perinatal risk factor which included intrauterine growth retardation and asphyxia. Complex phenotypic dysmorphic features were observed at birth. The phenotype of our patient includes multiple facial and skeletal disorders: midface retrusion, prominent forehead, frontal bossing, shallow orbits, downslanted palpebral fissures, narrow nasal bridge, large filtrum, micrognathia, small hands with short metacarpal bones and short distal phalanges of fingers with consequent brachydactyly, knee flexion contracture, pseudoarthrosis, calcaneovalgus deformity, thoracic scoliosis, lumbar hyperlordosis, coxa valga, skeletal dysplasia, pectus carinatum, generalized hypotonia, global developmental delay, cognitive impairment, complete lack of adipose tissue with consequent pseudohypertrophy of muscles, bilateral cataracts and progeroid facial appearance . As a paComputed tomography (CT) scan of cranio-cervical junction revealed bifid arch of the atlas as a part of skeletal disorders. Additional preoperative magnetic resonance imaging (MRI) revealed a critical stenosis of cranio-cervical junction with concomitant myelopathy .COG4 gene (16-70530270-C-T NM_015386.3:c.1546G>A (NP_056201.2:p.Gly516Arg). Amino acid changes identical to a pathogenic variant have been previously reported (ClinVarID: VCV000585271). The same variant was also reported as de novo in one or more affected individuals with a consistent phenotype from multiple, unrelated families.Karyotyping excluded chromosomopathies, and no change of clear clinical significance in chromosomal microarray analysis (CMA) was found. Whole exome sequencing  identified a pathogenic heterozygous variant in The patient underwent surgical treatment under general anesthesia and in a prone position. The surgical approach was performed in the mediosagittal plane. The foramen magnum was decompressed with a micro-technique using a high-speed drill and a rongeur . The bonThe postoperative recovery went uneventfully, and the patient was released from hospital one week after surgery.Follow-up MRI scan of cranio-cervical junction after three months and one year revealed residual stenosis of CCJ and myelopathy of cervical medulla. Nevertheless, the postoperative diameter of decompressed CCJ was insignificantly wider in the sagittal and axial planes compared to preoperative MRI scan .Saul-Wilson syndrome is considered one of the rarest diseases worldwide with only fourteen known cases from the 1990s until the present. Saul and Wilson were the first to describe the syndrome, which was presented as severely short stature, craniofacial dysmorphism and microcephaly . ClinicaIn the scope of the presented case conditioned by congenital disorders, further surgical approaches should be avoided, and further treatment should be focused merely on symptomatic treatment under guidance of paediatricians.A preoperative magnetic resonance imaging (MRI) scan revealed a severe myelopathy at the level of cranio-cervical junction and radiologic signs of atlanto-axial instability. Therefore, the authors decided to obtain only bone decompression of the foramen magnum and C1 vertebra to prevent any possible neurological deterioration with the aim of achieving a better radiologic outcome, e.g., partial or nearly complete regression of myelopathy. There were no radiological signs of platybasia and basilar invagination according to radiographic measurements of cranio-cervical junction.Despite an adequate decompression of the CCJ, a postoperative follow-up MRI scan revealed only a limited widening of the diameter of the cranio-cervical junction caused by radiologically confirmed atlanto-axial instability. There was no sign of regression of myelopathy. The authors did not confirm the utmost benefit of surgery according to radiological follow-up.Ferreira et al. compared and followed-up characteristics of their patients which revealed short stature and progeroid appearance in all patients. A significant part of SWS clinical findings are skeletal abnormalities, which are described as osteoarticular pain followed by decrease range of motion. Bone fragility and poor bone healing are also presented as secondary common clinical features in patients suffered from SWS . AccordiDespite satisfying postoperative recovery, the main obstacle in further treatment of our patient remained his established clinical status in the scope of his primary disease and radiologic confirmation of persisting myelopathy. Another significant difficulty in the treatment approach was the impossibility of obtaining a prompt genetical confirmation of SWS, since it currently cannot be performed in the Republic of Croatia. A genetic exam was necessary to obtain an adequate diagnosis due to the physical features and physical development of the patient. Goel proposed a classification of atlantoaxial instability based on analysis of numerous subjects that included instabilities of all spinal segments. A novel classification defines types of central atlantoaxial instability (CAAD) with emphasis on the possibility of atlantoaxial instability without radiologic confirmation or influence of bone deformity. There are two types of atlantoaxial instability that define dislocation of the atlas in the anterior or posterior direction (types 1 and 2), and a third type that defines normal anatomic alignment with clinical and radiological evidence during the surgical procedure (type 3). Furthermore, Goel described CAAD as an independent clinical entity and the cause of cervical myelopathy, especially in abnormal conditions of cervical spine, included bifid arch of the atlas which is comparable to our case. Musculoskeletal and neurologic alterations as the most common hallmarks in patients with CAAD are not considered as embryological disorders. Contrary to this claim, based on a large number of subjects, musculoskeletal and neurological disorders in our patient have to be considered as a result of primordial growth disturbance as a part of SWS .We were unable to surgically treat our patient properly due to his physical status, which included a very low bodily height and weight, shortened neck and soft bones, creating difficulties in achieving the usual operative approach. At the moment, the treatment of SWS remains mainly in the reach of paediatricians according to the clinical symptoms of the patient, mostly systemic and metabolic conditions.In conclusion, the authors were confronted with an unusual condition in an extremely rare congenital disease. Due to its rarity, a possible preoperative radiologic confirmation of critical stenosis of CCJ in such cases should be carefully evaluated. If required, surgery should only be considered as a palliative treatment.