Human Immunodeficiency virus (HIV)-associated neurocognitive disorders are a major burden for people living with HIV whose viremia is stably suppressed with antiretroviral therapy. The pathogenesis of disease is likely multifaceted, with contributions from viral reservoirs including the brain, chronic and systemic inflammation, and traditional risk factors including drug use. Elucidating the effects of each element on disease pathogenesis is near impossible in human clinical or ex vivo studies, facilitating the need for robust and accurate non-human primate models. In this review, we describe the major non-human primate models of neuroHIV infection, their use to study the acute, chronic, and virally suppressed infection of the brain, and novel therapies targeting brain reservoirs and inflammation. Although viral suppression with antiretroviral therapies (ARTs) has significantly improved HIV prognosis, people with HIV (PWH) still require long-term treatment and have a higher risk of comorbid disease compared to people without HIV . SpecifiThe mechanisms driving HANDs are unclear, partly due to a likely multifaceted disease pathogenesis which is difficult to define using ex vivo human studies alone. Therefore, the majority of our understanding of central nervous system (CNS) infection has been derived from autopsy material and cerebrospinal fluid (CSF) biomarker studies. It is thought that localized infection in the brain, shown to occur during acute infection, coupled with chronic systemic inflammatory mechanisms, may contribute to neuronal degradation and HAND pathogenesis. However, the paucity of brain tissue and the inherent inability to access longitudinal tissue samples in humans highlights the need for robust animal models to better define HAND pathogenesis.Non-human primate (NHP) models offer unique insight into the underlying and governing mechanisms of neurocognitive disorders for many diseases in a manner not possible in humans. For instance, the spontaneous NHP model of multiple sclerosis (MS), a characteristically difficult disease to study at a cellular level in humans, mimics the immunopathology of humans and has corroborated the role of a virus in demyelinating diseases . Recent NHP models infected with simian immunodeficiency virus (SIV) are the most physiologically relevant model of HIV. NHPs infected with SIV show similar disease pathogenesis to HIV, including the development of acquired immune deficiency syndrome (AIDS), gastrointestinal damage and traditional AIDS-defining illnesses and comorbid disease  development and anatomy analogous to humans, and when infected with strains of SIV display remarkably similar infection and disease progression to HIV infection ,24. ImpoAccelerated CNS viral strains rapidly infect the CNS and typically result in SIV encephalitis (SIVE) and full immunosuppressive disease over a period of months. For instance, the infection of pigtailed macaques with both SIV/17E-Fr (neurotropic) and SIV/ΔB670 (immunosuppressive swarm) results in neurological disease in approximately 90% of animals within 85 days post inoculation ,27,28. TPrimate lentiviruses  are dual receptor viruses that use both the primary CD4 receptor and a coreceptor  and by virtue of their ability to infect myeloid lineage cells as well as CD4+ T cells, establish infection within the CNS within 2 weeks post infection. NHPs infected with SIVmac251 or the molecular clone SIVmac239 will typically progress to AIDS within 1–2 years without ART, compared to 8–10 years for humans . AnimalsSimilar to the CD8+ T cell depletion model, the depletion of CD4+ T cells prior to SIVmac251 inoculation accelerates disease progression and severity in the CNS due to productive microglia infection . Alternaenv. SHIVSF162P3 is a CCR5-tropic virus that results in SIVE in 14% of infected animals [Whilst the SIV variants above model HIV infection, they still predominantly contain SIV viral genes and proteins, which are evolutionarily different to HIV and differ in their sensitivity to certain antiretroviral (ARV) drugs , which specifically target HIV-1 reverse transcriptase (RT) and do not effectively inhibit SIV RT ). Chimer animals . Due to NHP models of HIV have provided significant insight into early infection events in the brain as studies in PWH are exceptionally difficult and the diagnosis of infection is often made months after transmission events. Furthermore, characterizing viral penetration into the brain can only be defined by CSF viral load testing, which is invasive and may not reflect CNS tissue infection. Human ex vivo studies predict that HIV infects the CNS during early acute infection , with loNHP studies have further implicated T cells as a major source of viral infection into the CNS. RMs infected with the non-accelerated SHIV-1157ipd3N4 showed an infiltration of T cells and infected cells in the meninges following 12 weeks post infection . FurtherFollowing entry to the brain, HIV/SIV infects long-lived resident CNS cells such as perivascular macrophages, microglia, pericytes, and astrocytes ,68,69,70Acute SIV infection is associated with neuronal damage and activated astrocytes and microglia ,79; alteAltered CD8+ T cell responses during acute infection may also contribute to CNS pathogenesis during acute infection. The depletion of CD8+ T cells in multiple SIV NHP models accelerates CNS disease pathology and the administration of anti-CD8 monoclonal antibody in the CSF of SIV-infected animals has been shown to result in an increase in SIV DNA in the brain, and microglial activation . A recenIf left untreated, SIV infection in the CNS results in SIVE, which is characterized by multinucleated giant cells in the brain , mediated by nef , neuronaFinally, similar to findings in PWH, SIV infection is also associated with vascular dysfunction and cerebrovascular disease that may also affect the CNS. SIV infection is associated with endothelial activation and macrophage accumulation around vessels . FurtherThe contribution of the CNS as a long-lived reservoir of replication-competent SIV/HIV viral DNA (vDNA) to ART remains controversial in some circles. This is partly due to the reliance on well characterized autopsy material and difficulties in translating technologies to brain tissues. We and others have shown that brain cells, including microglia/perivascular macrophages, astrocytes, and pericytes from ART-suppressed individuals, harbour HIV DNA . We receNHP studies have further advanced our understanding of a viral reservoir in the brain of ART-suppressed animals . A comprPersistent vDNA+ cells are found in tissue reservoirs in the CNS and periphery, likely due to the inability of ART to target latent virus. The SIV brain reservoir was also demonstrated in the SIVE NHP model of the dual inoculation of SIV/ΔB670 and SIV/17E-Fr in pigtailed macaques . All aniWhether viruses present in the CNS are truly replication-competent and capable of producing infectious virions, thus contributing to subsequent cellular infection, is a major question in the field and exceptionally difficult to answer in humans ex vivo. Studies in human peripheral blood mononuclear cells (PBMCs) have demonstrated that the large majority of proviruses are replication incompetent  due to hypermutations and/or deletions in the genome . TherefoAlternatively, assays that measure functional HIV transcripts, full length genomes, viral proteins, or ultimately viral outgrowth in target cells are more indicative of the replication competence of viral reservoirs. Ex vivo human studies have detected HIV RNA in the CSF of ART-suppressed individuals, potentially related to ongoing viral replication in the brain. However, it is possible that these viruses are entering the CSF from the blood, and are therefore not truly reactivating viruses from the CNS. To date, the best evidence of possible replication-competent viral genomes in the CNS derives from NHP studies. A study using pigtailed macaques infected with SIV/ΔB670 and SIV/17E-Fr were virally suppressed for 500 days with ART followed by latency reversal treatment demonstrated increased CSF viral loads, supporting the activation of latent virus present in the CNS . In anotChronic immune activation and cellular dysfunction in the CNS likely persists following ART and is hypothesized to contribute to the pathogenesis of HANDs in ART-suppressed PWH. The low-level expression of the HIV tat protein promotes a neurodegenerative phenotype caused by a reduction in brain volume, astrocyte activation, inflammatory cytokine expression, as well as synapse and axonal damage ,105,106.To date, comparatively few studies have assessed the immune environment in the brain of ART-suppressed SIV-infected animals, and findings appear to differ depending on the models used. As described above, untreated SIV infection generally is associated with elevated immune activation, oxidative stress, and cellular dysfunction. Several studies using accelerated infection models show that ART treatment reduces the level of inflammatory cytokines compared to untreated SIV infection; however, levels remain elevated in ART-treated animals relative to SIV-uninfected controls ,115. SpeConversely, several studies have found that ART treatment results in the near complete resolution of heightened immune activation in the brain. Mx2, superoxide dismutase 2 (SOD2), TNFα, and CCL2 levels in the brain of ART-treated SIV-infected RMs were similar to uninfected controls in contrast to heightened levels in ART-naïve animals, supporting the idea that ART treatment dampens SIV-infected immune activation in the brain ,116,117.The gut is one of the first major sites of viral replication following HIV infection due to its high density of HIV susceptible CD4+ T cells ,120. TheThis physical and immunological damage to the gut impairs mucosal integrity resulting in a “leaky gut” whereby microbes and their products such as lipopolysaccharide (LPS) can translocate through the enterocytes and between epithelial cells into the blood stream. The resulting gut dysbiosis persists despite ART ,125,126,Studies in humans indicate that some ART compounds do not penetrate the brain, which may lead to pockets within deep tissue sites including the brain where HIV/SIV may be able to replicate, drive immune activation, and contribute to neurocognitive decline ,93,138. PWH have higher rates of illicit drug use than HIV-seronegative individuals, which may potentiate HAND pathogenesis. Importantly, the use of SIV animal models has allowed for the controlled assessment of each modifiable risk factor on neuropathogenesis, where morphine use, methamphetamine use, smoking, and even age have been linked to neuropathogenesis in SIV-infected animal models. Specifically, morphine use accentuates SIV neuropathology including higher levels of the infiltrating of myeloid cells in the brain during acute infection relative to SIV-infected animals who were not treated with morphine . InteresCognitive and behavioral testing is essential in characterizing the pathogenesis of the milder forms of HANDs. However, the evidence of the suitability and applicability of NHP models of HIV to study cognitive impairment is limited. NHPs infected with neurovirulent strains of SIV (SIV/17E-Fr + SIV/ΔB670) and experimentally induced encephalitis have shown deficits in motor control and spatial working memory with similarities to PWH ,149,150.Broader behavioral testing used in NHP models of other cognitive disorders in the absence of encephalitis may offer translational benefit for modelling mild HANDs. In humans, HAND diagnosis includes a battery of cognitive testing that spans multiple cognitive domains including: verbal/language; attention/working memory; abstraction/executive; memory ; speed of information processing; sensory–perceptual; and motor skills . AlthougIn contrast to SIV models, behavioral testing in NHP models of other neurocognitive disorders such as Huntington’s and Parkinson’s disease are more well-established and may be applicable to chronic SIV. Specifically, cognitive impairment and anxiety-like behavior have been described in a transgenic NHP model of Parkinson’s disease . BehavioOne major benefit of utilizing NHP models of SIV/SHIV infection is the flexibility to perform intervention studies to target SIV brain infection and/or inflammation. Reactivating latent HIV in circulating CD4+ T cells as part of ‘shock and kill’ strategies have been tested in vitro and in vivo in NHPs. However, comparatively little is known regarding targeting reservoirs in the brains of SIV-infected animals.The treatment of SIV-infected animals with the second mitochondria-derived activator of caspases (SMAC) mimetic AZD5582 induced reactivation of viral reservoirs in the blood and tissue of ART-treated animals . Whilst Another cutting-edge technique that highlights the necessity of using NHP models for developing novel R&D is a recent proof-of-concept for utilizing CRISPR/Cas9 to reduce the amount of proviral DNA present within the brain and CNS . With eTreatments selectively targeting neuroinflammation and oxidative stress in the brain have had some benefit in SIV-infected NHPs. Meulendyke and colleagues identified fluconazole and paroxetine (FluPar) as protective compounds against gp120 and tat neurotoxicity . This trFinally, targeting systemic inflammation, characteristic of chronic HIV/SIV infection, may also be of benefit in improving neuroSIV pathogenesis. The treatment of SIV-infected animals with drugs designed to target microbial translocation via controlling microbes or gut inflammation  showed benefit in lowering systemic immune activation and microbial translocation during acute infection ; howeverThe mechanisms contributing to viral persistence, neuroinflammation, and cognitive disorders in PWH remain a tangled web that is difficult to delineate in human ex vivo studies alone. Thus, clinically and physiologically relevant NHP models are essential tools required to define the relationship between mild neurocognitive disorders, CNS viral burden, systemic inflammation, and immune activation in the brain. Understanding the roles and contributions of each element to ongoing brain disease will guide further therapeutic interventions with translational capacity for people living with chronic HIV and HANDs.


Age-related disorders of the musculoskeletal system including sarcopenia, osteoporosis and arthritis represent some of the most common chronic conditions worldwide, for which there remains a great clinical need to develop safer and more efficacious pharmacological treatments. Collectively, these conditions involve multiple tissues, including skeletal muscle, bone, articular cartilage and the synovium within the joint lining. In this review, we discuss the potential for oligonucleotide therapies to combat the unmet clinical need in musculoskeletal disorders by evaluating the successes of oligonucleotides to modify candidate pathological gene targets and cellular processes in relevant tissues and cells of the musculoskeletal system. Further, we discuss the challenges that remain for the clinical development of oligonucleotides therapies for musculoskeletal disorders and evaluate some of the current approaches to overcome these. Oligonucleotide therapeutics represent a relatively novel class of drug, with the potential to modulate drug targets that were previously considered intractable, and with the benefit of fast clinical development times. In this review, we consider the opportunities for the development of oligonucleotide therapeutics for the treatment of age-related musculoskeletal disorders including osteoarthritis (OA), rheumatoid arthritis (RA), osteoporosis and sarcopenia. With the focus on the tissues of the musculoskeletal system, namely skeletal muscle, cartilage, bone and synovium, we evaluate the successes and challenges of oligonucleotide modalities to modulate target gene expression and ultimately to provide therapeutic efficacy.Sarcopenia, the age-related decline of skeletal muscle mass and strength, is a major contributor to increased frailty, longer hospitalisation and poor healthspan ,2,3. FurThe drivers of sarcopenia are multifactorial and include inherent biological ageing, obesity ,10, reduMaintenance of healthy bone requires efficient bone remodelling, a process constantly performed by bone forming osteoblast and bone resorbing osteoclast cells. Disrupting the delicate balance between osteoblast and osteoclast activity in favour of bone resorption can lead to the development of osteopenia and eventually osteoporosis, characterised by a significant reduction in bone mineral density and deterioration of the trabecular bone microarchitecture. Osteoporosis is primarily an age associated disease, with bone mass beginning to decline from around the age of 40 in the absence of loading stimuli such as resistance exercise . AdditioBisphosphonates are the first line treatment for individuals with osteoporosis, acting to reduce bone resorption through increasing apoptosis of osteoclasts . HoweverArthritis can be broadly classified into two categories, immune-mediated inflammatory arthropathies such as RA, and degenerative arthritis, which is synonymous with OA. In all cases, patients experience joint pain and joint stiffness, leading to progressive joint degeneration and disability . GloballAs a systemic chronic autoimmune disease, RA is characterised by inflammation of the synovium joint lining, termed synovitis, which occurs predominantly in the small joints . The expImportantly, despite historically being seen as solely a wear and tear degenerative disease of the cartilage, it is now widely accepted that OA is a disease of the whole joint, encompassing the synovium, subchondral bone, skeletal muscle as well as the cartilage . AlthougThe treat-to-target therapeutic management of RA patients aims to reduce pain and improve joint function by targeting immune activity and inflammation utilising corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs) and biologics . HoweverSuccesses in the use of oligonucleotides to modulate relevant gene targets and cellular processes in vitro, as well as those oligonucleotides that have demonstrated in vivo efficacy for the major tissues of the musculoskeletal system, including skeletal muscle, bone, cartilage and synovium  are detaThe most investigated target for oligonucleotide therapeutics against sarcopenia is myostatin , which acts as a negative regulator of muscle growth in an endocrine and autocrine manner . An earlA range of knock-down strategies and delivery technologies have been tested for myostatin-targeted oligonucleotides. Antisense RNAs targeting the start site, termination site or inducing exon skipping have proven efficacy to increase muscle mass in normal mice ,63. AddiA few studies have explored oligonucleotides targeting other mediators in the myostatin signalling pathway. Liu et al. showed that targeting Foxo-1 with 2′-O-methyl antisense RNAs (100 µg i.v twice-weekly for 4 weeks) effectively suppressed myostatin, induced the myogenic factor MyoD and increased skeletal muscle mass in normal and cancer-bearing cachectic mice . InvestiSenescence can deplete the pool of precursor muscle satellite cells that are essential for the maintenance and regeneration of muscle mass . Price eThe balance between protein synthesis and degradation is disturbed in sarcopenia, with suppression of the anabolic IGF-1/insulin-pAkt-mTOR signalling pathway and activation of the catabolic ubiquitin-proteosome system . The latOne mechanism to reduce bone resorption is to prevent osteoclast formation by inhibition of NF-κB (a positive regulator of osteoclastogenesis) in myeloid lineage cells present within the bone marrow . ShimizuOsteoporosis and osteolysis have also been demonstrated to occur secondary to cancer, particularly following metastasis to bone ,93. One Chronic glucocorticoid treatment can also drive osteoporosis, via an upregulation of osteoclastogenesis, coupled with increased osteoblast apoptosis and impaired osteoblast differentiation and dysfunction ,98,99. AIn contrast to inhibiting osteoclast function and bone degradation as discussed so far, the alternative approach to increase bone mass via promoting an increase in bone synthesis. DKK1 is a negative regulator of bone formation, acting to inhibit the Wnt receptor and the low-density lipoprotein receptor-related protein 5 (LRP5) co-receptor complex formation of the canonical Wnt signalling pathway . Consequ2 or 2 ng VEGF/mm2 were immobilized on the orthopaedic implant surface) [Finally, in addition to oligonucleotide mediated modulation of cellular function, a novel use of oligonucleotides in bone biology could be to deliver bone promoting factors to the site of implantation during joint replacement therapy to prevent aseptic loosening, a major complication of such procedures. To this end, Wolfle et al. coated oligonucleotides onto the surface of titanium implant material. These oligonucleotides had a complementary sequence to other oligonucleotides conjugated to BMP2 and VEGF, thus enabling localised delivery of these factors to the native bone microenvironment upon implantation (2 ng BMP2/mmsurface) . Utilisisurface) .Collectively, there is evidence that oligonucleotide targeted therapy may offer a novel therapeutic approach to both prevent bone breakdown through inhibition of osteoclast activity and increase bone mass through increasing bone formation in osteoblasts. Continued development of such oligonucleotide treatments could provide valuable tools to maintain bone mass in individuals at risk of osteoporosis and osteolysis. However, it is evident that studies utilising primary human bone cells and progress to clinical trials are now required.Degeneration of the articular cartilage is a characteristic feature of arthritis, most notably in OA. Articular cartilage, unlike most tissues within the human body, is devoid of blood vessels, nerves and lymphatics. Instead, it is made of dense layers of extracellular matrix  which in healthy tissue is maintained by specialised cells known as articular chondrocytes. This proteoglycan rich matrix is hydrated with water, providing the cartilage with its load-absorbing properties. In OA, chondrocytes adopt a hypertrophic phenotype, and cartilage homeostasis is disturbed by increased production of MMPs such as MMP3 and MMP13 and aggrecanases ADAMTS 4 and ADAMTS5 , which dIn vitro studies using human chondrocytes have shown that stromal cell-derived factor (SDF)-1 mediated MMP13 induction can be reduced either using siRNA targeting the SDF-1 receptor CXCR4, or using antisense oligonucleotides (ASO) targeting transcription factors c-Fos and c-Jun to inhibit MMP-13 promoter activity . FurtherIn vivo, several candidate oligonucleotide therapies designed to reduce cartilage degeneration have been studied in preclinical animal models of arthritis. In an anterior cruciate ligament (ACL) rodent model, inhibiting miR-29b-3p using an intra-articular injection of miR-29b-3p antagomir (800 pmol) ameliorated chondrocytes apoptosis and cartilage loss through targeting of PGRN . SimilarIn arthritis, the synovium undergoes a number of pathological changes including increased proliferation of resident synovial fibroblasts, angiogenesis and vascularisation and increased infiltration of inflammatory immune cells, which drive a chronic inflammatory state within the synovial joint termed synovitis . Pro-infIn vitro studies have demonstrated the efficacy of antisense oligonucleotides in modulating the inflammatory synovial fibroblast phenotype. In one such study, a locked nucleic acid (LNA) antisense targeting the long non-coding RNA MALAT1, which is highly expressed in obese inflammatory OA synovial fibroblasts, resulted in reduced expression of CXCL8 and reduced proliferation . SimilarAn alternative approach to combating synovitis is to target the hyperplastic nature of arthritic synovial fibroblasts. To accomplish that, inhibition of the anti-apoptotic protein FLICE-inhibitory protein (FLIP) using a phosphorothioate-modified oligodeoxynucleotide (5 µM for 24 h) was found to sensitize RA synovial fibroblasts to Fas-mediated apoptosis . SimilarTo date, despite the plethora of in vitro studies that have demonstrated the efficacy of oligonucleotides to target and modulate the activated synovial fibroblast pathotype, very few oligonucleotide therapeutics have transitioned into demonstrating efficacy in targeting the synovium in preclinical in vivo models. Of those that have, research conducted by Weng et al., targeted DKK1, the Wnt signalling pathway inhibitor, in a surgically induced experimental model of OA . IntrapeOligonucleotides have huge therapeutic potential for treatment and management across many conditions. Their capacity to selectively bind both by complementary base pairing to target sequences as well as through 3D secondary structures to specific proteins are largely exploited for gene silencing . CurrentStability of oligonucleotides once administered is a particular limiter in clinical translation and depends on protecting nucleic acids from nuclease degradation using chemical modifications and conjugates of peptides, lipids and polymers . First gAnother major obstacle in oligonucleotide therapeutics is efficient delivery to target tissues. Due to their hydrophobic nature, oligonucleotides do not pass through the plasma membrane . Thus, sInterestingly, the delivery of FDA-approved oligonucleotide therapeutics largely depends on chemical modifications for tissue delivery as discussed earlier. To this end, second-generation gapmer antisense oligonucleotides have been extensively modified to facilitate delivery to a variety of tissues without a delivery agent . Other sMore recently, antibody conjugates, which have had success with the targeted delivery of cytotoxic drugs (ADCs), are now also being considered for the targeted delivery of oligonucleotides, termed antibody oligonucleotide conjugates (AOCs) . Such ADGreat strides have been made in modifying oligonucleotides to improve their stability in vivo. However, for age-related musculoskeletal disorders, challenges remain in improving the ability of oligonucleotides to effectively penetrate the tissues of the musculoskeletal system. Furthermore, the selective targeting of specific cell types or, with the advent of single cell data, the desire to target specific cell subsets represents a significant hurdle at present. Overcoming these hurdles is currently the focus of much research and will likely be met via the development of novel bioconjugation strategies. Clearly, with the many advantages offered by oligonucleotide therapeutics including their rapid development time, encouraging safety profiles, intrinsic mode of action in targeting genes prior to their translation into proteins, and recent approvals of oligonucleotide-based drugs in other therapy areas, this investment is warranted. Perhaps most importantly though, within the unmet clinical need of musculoskeletal disorders they open the door to an array of previously intractable targets, thus offering new and exciting therapeutic strategies.


Breast cancer is a leading cause of morbidity and mortality in women worldwide, with mortality rates largely driven by metastatic disease. Despite concerted efforts to uncover and target the mechanisms underlying these events, the five-year relative survival rate for metastatic breast cancer remains an abysmal 27%. To better inform future directions for managing this disease, it is helpful to examine the evolution of cancer research, from foundational concepts to therapies and their pitfalls. This review aims to provide a rich overview of the history of breast cancer therapies spanning antiquity to the modern era, concluding with the rapid advancements in immunotherapies and our eventual progression towards personalized medicine.An examination of the origins of medical approaches to breast cancer marks this disease as one of the most difficult to manage. As the early identification, diagnosis and treatment of breast cancer evolve, we will move to a time when each patient and their cancer can be assessed to determine unique patient-specific  approaches to therapy. Humans have attempted to manage breast cancer for millennia. Even today, the disease claims thousands of lives each year. In light of the increasingly sophisticated understanding of cancer diagnosis and treatment, together with our ultimate failure to offer a cure in the most difficult cases, it is instructive to reflect on the beginnings of our understanding. Edwin Smith Surgical Papyrus by the infamous Egyptian physician Imhotep himself [Long regarded as a symbol of allurement and fertility, few aspects of the human physique are subject to greater praise and scrutiny than the female breast. Under the sharpened gaze of a physician-scientist, however, the breast renders a unique quandary dating back to the 17th century B.C.E. Perplexed by incidences of a disfiguring and incurable malady of the breast, ancient Egyptian physicians were among the first to note the organ with medical interest. Some experts contend that these first accounts of breast cancer were recorded in the  himself . The Egycarcinos nomenclature first introduced by his predecessor. The modern derivation of the term oncology originated from Galen’s usage of the Greek word oncos, meaning swollen, to describe all tumors [Ancient Hellenistic writings further documented early cases of breast cancer and introduced the usage of modern medical terminology to describe carcinoma and metastatic disease . The worl tumors . Galen’sl tumors . Medical practice in the subsequent millennium (c. 500–1500 C.E.) was dominated by the dissemination of religious philosophies that favored faith-based healing over the seemingly barbaric nature of invasive surgery. During a period marked by surgical stagnation, cauterization and application of arsenic-containing caustic pastes were preferred treatments for tumors of the breast . The invCases of lumpectomies, mastectomies, and axilla removal began to fill European medical records, having been touted by prominent surgeons such as Jean Louis Petit (1674–1750) and Lorenz Heister (1683–1758) . The 19tDie Cellularpathologie (1858), describing the cellular origins of cancer [Lectures on Tumours (1851) and Lectures on Surgical Pathology (1853) [On Disease of the Mammary Areola Preceding Cancer of the Mammary Gland [The theory that lymph and cancer were synonymous entities greatly weakened after German pathologists Johannes Muller 1801–1858) and Rudolf Virchow 1821–1902) detailed a cellular basis for tumors . A prolif cancer . Virchowy (1853) ,17. Page01–1858 a02 detailry Gland .Recherches sur le Traitement du Cancer [The Distribution of Secondary Growths in Cancer of the Breast (1889) that metastatic tumor cells, despite being ubiquitous in the bloodstream, only grew at compatible tissue sites. Similar to a plant’s seeds being disseminated by the wind, Paget argued that malignant cells carried by blood preferentially survived and grew through elected interaction with the “congenial soil” of remote organs [A comprehensive understanding of how cancers spread remained a lacking feature of the early 19th century. In his 1829 publication u Cancer , French u Cancer . Karl Thu Cancer . Not to u Cancer . Paget ce organs . Having pectoralis major to limit further recurrence [On Treatment of Inoperable Cases of Carcinoma of the Mamma, Beatson’s findings were among the first to suggest anti-hormonal treatment for advanced breast cancer [Expanding knowledge on cancer’s cellular origins heralded a blossoming awareness for more sophisticated treatment regimens. As a result, the late 19th and early 20th centuries saw major advancements in both surgical and alternative therapies for breast cancer . In 1894currence ,25,26. Hcurrence . Popularcurrence ,29. A shcurrence . Surgicat cancer . A series of seminal discoveries made at the cusp of the 20th century birthed a new paradigm for cancer treatment and revolutionized modern oncology. Following the discovery of X-rays in 1895 by Wilhem Roentgen (1845–1923), scientists across the globe raced to understand and harness the properties of radiation. Emerging at the forefront were French physicists Henri Becquerel (1852–1908) and Pierre Curie (1859–1906), and Polish-French physicist and chemist Marie Sklodowska Curie (1867–1923) . The triPierre and Marie Curie’s discovery of radium and polonium, which earned the latter the 1911 Nobel Prize in Chemistry, further contributed to the use of radiotherapy to combat cancer. In contrast to the X-ray, which could only be administered over a broad surface, radium could be delivered locally, topically , and interstitially (via radium emanating rods) . Thus, rtherapia sterilisans magna” (great sterilizing therapy) for the treatment of bacterial disease [The conception of chemotherapy can be ascribed to the prominent chemist Paul Ehrlich (1854–1915), whose research aimed to discover a “ disease . With it disease . Using a disease ,48,49. I disease . While t disease .Goodman and Gilman’s early work on nitrogen mustard fed the frenzy to screen the compound, its derivatives, and alternative chemical agents in animal models of cancer as well as in patients. The latter half of the 20th century saw the emergence of several new chemotherapies whose development was largely supported by WWII-related initiatives . NutritiSeveral other chemotherapies seemingly materialized overnight and were rapidly approved by the U.S. Food and Drug Administration. Among these, the purine analogue 6-mercaptopurine synthesized by Gertrude Elion (1918–1999) was used against childhood leukemia and earned Elion the 1988 Nobel Prize ,56. ThisTo combat waning support throughout the next decade, medical oncologists curated new applications for chemotherapy. Combination chemotherapy emerged in the late 1960s as a viable treatment for advanced breast cancer , with a Streptomyces bacteria gained international fame for exerting broad anti-tumor effects across several cancers [Spurred by renewed public interest on the “war on cancer” and the passage of the National Cancer Act in 1971, new classes of chemotherapies were rapidly introduced and approved for patient use. The application of improved screening models, including the use of human xenografts in nude mice, was critical to shaping their success ,70. Duri cancers . Known a cancers . Moreove cancers . Taxus brevifolia (the Pacific yew tree), paclitaxel and docetaxel were shown to induce cell cycle arrest by stabilizing tubulin and preventing mitotic division [In addition to the anthracyclines, the taxanes encompass another class of anti-tumor compounds isolated from natural sources that demonstrated clinical success. Originally derived from division ,76,77. Tdivision .Support for a hormonal basis for cancer burgeoned half a century after Beatson’s original studies on applying oophorectomy to treat breast cancer. Critical work led by Charles Huggins (1901–1997) at the University of Chicago demonstrated regression of metastatic prostate carcinoma following removal of the testes ,80. HuggIn 1966, an accidental discovery made by scientists at the England-based ICI Pharmaceuticals led to the development of the first anti-estrogen compound that later became the gold standard in breast cancer treatment. In an effort to screen potential anti-fertility compounds for contraceptive use, a team led by Arthur Wapole identified a potent anti-estrogen previously synthesized and supplied by organic chemist Dora Richardson. Compound ICI 46,474 later proved ineffective as a contraceptive, but at Wapole’s insistence, was carried into preclinical and phase II clinical trials for palliative treatment of advanced breast cancer . FurtherSubsequent years saw the development of other SERMs, in addition to a new class of estrogen-modulating compounds for the treatment of advanced breast carcinoma. The discovery that testosterone could be converted to estrogen through a process called aromatization laid the foundation for further research into aromatase inhibitors ,94,95,96The introduction of DNA and genome sequencing technologies during the late 1960s led to the identification of numerous genetic targets for therapeutic intervention. Identification of the first oncogene in 1970 bolstered the search for additional oncogenes and proto-oncogenes regulating growth factor signaling and carcinogenesis ,106. TheThe 2018 Nobel Prize in Physiology and Medicine was awarded to James Allison and Tasuko Honjo, two immunologists whose original discoveries significantly impacted modern cancer treatment. Thus, it might seem startling that a glimpse into their nascent careers would reveal pervasive skepticism surrounding the notion of immune modulation to combat cancer . Indeed,The establishment of the New York Cancer Research Institute in 1953 by Coley’s daughter, Helen Coley Nauts, supported the re-emergence of harnessing the immune system to treat cancer . These eThe immuno-oncology field slowly garnered interest after multiple independent studies identified the Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) as a negative regulator of T cell activation and proliferation ,131. In In the years leading up to the discovery of CTLA-4 as a critical immune regulator, an independent team at Kyoto University had taken similar steps to characterize a related and then-unknown immune checkpoint. Led by Tasuko Honjo, the group was credited for isolating Programmed Cell Death 1 (PD-1) on murine T cells and was among the first groups to identify its involvement in autoimmune function and negative regulation of T cell activation ,136. SubCurrently, over a dozen immunotherapies have been approved for use in various cancers, including melanoma, hematological malignancies, and cancer of the lung, liver, bladder, colon, stomach, head and neck. Additional FDA approval has enabled their use as second- and third-line therapies in cases of multiple chemoresistance or as indicated by positive biomarker expression. While immunotherapies have achieved remarkable success in several of these cancers, overall response to these therapies in breast cancer remains modest . The lacNevertheless, multiple modalities of immune-based therapies for breast cancer are currently being evaluated in multi-phase clinical trials, including adoptive T cell therapy, preventative vaccines, and immune checkpoint blockade. In addition to those already tested in clinical trials, other emerging therapies involve the use of Chimeric Antigen Receptor-engineered T (CAR-T) cells, oncolytic viruses, and exogenous interferon delivery . StemminThe 21st century has seen modern cancer therapies flourish, from the novel application of targeted and combination chemotherapies to the development and delivery of near-curative immunotherapies. Invigorating still are the vast technologies and therapies positioned on the horizon. Where just decades prior scientists struggled to elucidate the basic structure of DNA, modern-day researchers have unraveled complexities in its organization, regulation, and processing that were previously deemed inconceivable. The convergence of epigenetics, diet, lifestyle, environmental exposures, and inherited factors is now widely recognized as predicting risk and survival outcomes. The clinical manifestation of this knowledge has birthed a new paradigm of personalized medicine that prioritizes the individual patient when deciphering available treatment options.No longer shrouded in complete mystery, tumor cells, and their respective host environments are now being illustrated in vivid detail. Real-time assessment of circulating tumor cells, DNA and various biomarkers weaves an epic tale of tumor evolution and overall disease progression. This information guides modern-day treatment and enables the precise deployment of second- and third-line therapies to combat drug-induced resistance. Further, a plethora of biomarker panels are currently in development and being tested for application in early cancer diagnosis and risk assessment. Emergent nanotechnologies have directly facilitated these events and include novel detection-based systems designed to push the limits of bioassay sensitivity.Despite achieving improved remission rates over the past two decades, cancer researchers and clinicians continue to face significant hurdles in their efforts to develop preventative and curative therapies. Among these challenges, the development of therapeutic resistance continues to perplex researchers and plague patient response. Nevertheless, emergent knowledge on tumor–stromal interactions and their spatiotemporal evolution in the face of therapy will undoubtedly inform novel treatment approaches to avert adaptive resistance. Further, as researchers’ toolkits continue to expand and intersperse across disciplines, the need to assimilate and interpret a growing sea of data remains critical. Thus, an imminent priority lies in curating new platforms and pipelines for data acquisition, management, and integration into the clinic.


Despite progress in understanding the pathogenesis of atherosclerosis, the development of effective therapeutic strategies is a challenging task that requires more research to attain its full potential. This review discusses current pharmacotherapy in atherosclerosis and explores the potential of some important emerging therapies  in terms of clinical translation. A chemopreventive approach based on modern research of plant-derived products is also presented. Future perspectives on preventive and therapeutic management of atherosclerosis and the design of tailored treatments are outlined. Atherosclerosis is currently recognized as a progressive metabolic and immune-inflammatory disease that affects the intimal lining of medium- and large-sized arteries ,2,3. It Pathobiology of atherosclerosis involves crosstalk between lipid metabolism imbalance, endothelial dysfunction, inflammatory pathways, oxidative stress and genetic predisposition. Endothelial cells, inflammatory cells and vascular smooth muscle cells (VSMCs) play key roles in disease development and progression. The main events that occur in atherogenesis are illustrated in Healthy endothelium is a major regulator of vascular homeostasis, releasing a wide spectrum of factors that control vascular tone and permeability, fluid balance, cellular adhesion, thromboresistance and fibro-inflammatory-proliferative responses. Endothelial-derived nitric oxide (NO) is a major factor that promotes vasoprotective and anti-atherosclerotic behavior ,16. ClasMonocytes/macrophages. Recruitment of circulating monocytes within the intima is elicited by the retention of lipoproteins and is one of the earliest atherogenic events; this process continues in subsequent stages of disease progression. Monocyte chemoattractant protein 1 and 3 (MCP-1 and -3) chemokines are implicated in monocytic chemotaxis to damaged vascular areas . I. I128]. ovibrio) . The mecAmong plant bioactives, phenolic compounds  appear to more potently modulate simultaneous signaling and mechanistic pathways in atherosclerosis. Further, dietary intervention trials support their protective effect in cardiovascular risk . Daily iOur review provides updated information on atherosclerosis and current pharmacotherapeutic approaches. In spite of remarkable progress achieved in understanding the mechanisms underlying the complex pathogenesis of atherosclerosis, the development of successful anti-atherosclerotic therapies remains a challenging task. Current therapeutic interventions are focused on improving lipoprotein metabolism and on modulation of atherosclerosis progression. Apart from statins, emerging therapies based on some cytokine-targeted agents  are also included in clinical practice. Another interesting emerging strategy is theranostics, which allows simultaneous treatment and imaging, promising an efficient approach to atherosclerosis and cardiovascular diseases. However, theranostics needs additional research, especially encompassing systemic toxic effects and the nanomaterial manufacturing process prior to clinical use. The establishment of chemopreventive strategies in atherosclerosis is also of paramount importance since prophylaxis is more beneficial than trying to reduce atherosclerotic lesions and plaque. The inclusion of documented and well-characterized plant products as components of these preventive programs could be a valuable intervention. Besides the effect of standardized plant products as an add-on therapy to conventional medicines, they could be an interesting avenue for the development of new therapeutics. The design of personalized treatments based on the concept of so-called “network medicine”—that includes the analysis and integration of genetic, metabolic and epigenetic factors—has been suggested as a more effective and appropriate therapeutic strategy in atherosclerosis .


Histopathologic and molecular features such as histological type, PD-L1 expression, and tumor mutation burden (TMB), play a paramount role in selecting appropriate regimens for cancer treatment in the era of immunotherapy. Unfortunately, none of the existing features are exclusive predictive biomarkers. Thus, there is an imperative need to pinpoint more effective biomarkers to identify patients who may achieve the most benefit from ICIs. The adoption of digital pathology in clinical flow, as being powered by artificial intelligence (AI) especially deep learning, has catalyzed the automated analysis of tissue slides. With the breakthrough of multiplex bioimaging technology, researchers can comprehensively characterize the tumor microenvironment, including the different immune cells’ distribution, function, and interaction. Here, we briefly summarize recent AI studies in digital pathology and share our perspective on emerging paradigms and directions to advance the development of immunotherapy biomarkers.Immune-checkpoint inhibitors (ICIs) have revolutionized the treatment of many malignancies. For instance, in lung cancer, however, only 20 Immunotherapy by immune-checkpoint inhibitors (ICIs) is a revolutionary cancer treatment that harnesses the body’s immune system to fight against cancer cells, which has transformed the landscape of cancer treatment . HistopaWith the rapid development of hardware and software for whole side imaging (WSI), particularly since the Food and Drug Administration (FDA) approved the WSI system to be used for primary diagnosis in 2017 . ArtificRoutine Hematoxylin and Eosin Staining (H&E): H&E is commonly used to reveal the nuclei morphology, and from which tumor-infiltrating lymphocytes (TILs) have demonstrated strong clinical values related to immunotherapy in various tumor types. There are ongoing efforts to automate TILs scoring from H&E slides using various CNN models , which cImmunohistochemistry (IHC) Staining: PD-L1, as one of the most studied biomarkers, is clinically used to stratify immune-checkpoint inhibitors (ICIs) based therapies in lung and other cancer types . There aNext Generation Multiplex Bioimaging: Multiplex techniques can simultaneously profile dozens of proteins in situ, enabling the systematic study of cellular compositions, functions, and interactions . The mulIn addition, multiplex imaging and analytics systems have been used to interrogate biological underpinnings for breast cancer progression from the pre-invasive stage  and the The information from a single platform or modality will carries limited information to characterize the patients. It will be a fruitful direction to combine the H&E with multiplex imaging to better profile TME. Moreover, such integration can be extended to various medical data, including radiomics, genomics, and electronic health records clinical data  Figure . We enviIt is well known that cancer is not just one disease but a group of distinct molecular or pathological subtypes. Given the rich immunogenomic data, six immune subtypes were identified across 33 cancer types . SimilarInnovations in digital pathology technology and AI have presented an unprecedented opportunity to advance biomarker development in immunotherapy. Though these approaches have demonstrated promising results, AI in digital pathology is still in its infancy. Data security and privacy put additional challenges to training and validating robust biomarkers in a multicenter setting of heterogeneous protocols. Powered by emerging federated learning , it beco


Women with coronary artery disease tend to have a worse short and long-term prognosis relative to men and the incidence of atherosclerotic cardiovascular disease is increasing. Women are less likely to present with classic anginal symptoms when compared with men and more likely to be misdiagnosed. Several non-invasive imaging modalities are available for diagnosing ischemic heart disease in women and many of these modalities can also assist with prognostication and help to guide management. Selection of the optimal imaging modality to evaluate women with possible ischemic heart disease is a scenario which clinicians often encounter. Earlier modalities such as exercise treadmill testing demonstrate significant performance variation in men and women, while newer modalities such as coronary CT angiography, myocardial perfusion imaging and cardiac magnetic resonance imaging are highly specific and sensitive for the detection of ischemia and coronary artery disease with greater parity between sexes. Individual factors, availability, diagnostic performance, and female-specific considerations such as pregnancy status may influence the decision to select one modality over another. Emerging techniques such as strain rate imaging, CT-myocardial perfusion imaging and cardiac magnetic resonance imaging present additional options for diagnosing ischemia and coronary microvascular dysfunction. Cardiovascular disease is the leading cause of death and disability, accounting for approximately one in three deaths worldwide . It is tThe pathogenesis of atherosclerosis begins in adolescence and early adulthood in the form of fatty streaks, long before manifesting as clinically overt disease . Lipid-rMI with nonobstructive coronary arteries (MINOCA) accounts for 5–10% of MI. Similarly, myocardial ischemia may occur with signs and symptoms of ischemia in the absence of significant CAD which is classified as ischemia with no obstructive coronary artery disease (INOCA) .There is likely some degree of overlap between MINOCA and INOCA. MINOCA is defined by criteria for the universal definition of MI, in which there is rise and/or fall of cardiac troponin (cTn) value above the 99th percentile with signs and symptoms of myocardial ischemia. This can be manifested as new ischemic ECG changes, new ischemic wall motion abnormalities, the loss of viable myocardium on noninvasive imaging, or identification of coronary thrombus by angiography or autopsy without obstructive coronary artery stenosis (<50% stenosis) on angiography, and the absence of myocarditis or Takotsubo cardiomyopathy . In contINOCA is characterized by the presence of angina with non-obstructive CAD  <0.8) on angiography. Approximately 60% of patients with INOCA are women. INOCA may occur alone or in combination with hypertension, severe aortic stenosis, severe anemia, coronary vasospasm, and myocardial bridging . In the Coronary microvascular dysfunction (CMD) is another etiology of IHD in women and is characterized by epicardial, microvascular endothelial or non-endothelial dysfunction. This leads to decreased coronary perfusion which can be detected as reduced coronary flow reserve (CFR). CFR is defined as the maximal increase in flow through the coronary arteries above the normal resting volume which reflects the ability of the coronary circulation to respond to increased oxygen demand. Positron emission tomography (PET) imaging remains the standard method for estimating CFR, although single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), intravascular Doppler ultrasound and echocardiography have been used . A ratioSpontaneous coronary artery dissection (SCAD) results from the separation of the intima and media due to hematoma formation within the medial layer causing external compression of the true coronary arterial lumen resulting in myocardial ischemia and/or infarction. SCAD is likely caused by a combination of various genetic, hormonal, arteriopathy and environmental factors. It is commonly associated with fibromuscular dysplasia which is predominantly seen in female patients. A small minority of cases are attributable to inherited connective tissue disorders such as Marfan, Loeys-Dietz and Ehlers-Danlos . SCAD deWomen with IHD can present differently when compared to men. Women are less likely to present with classic chest pain (31% compared with 42% in men) and more often report dyspnea, weakness, back pain, palpitations, or loss of appetite. Importantly, patients with ACS who present without chest pain are more likely to be misdiagnosed and have a higher risk of death than those who present with classic chest pain symptoms. Moreover, the absence of chest pain has not been consistently correlated with ACS severity ,22.There are a variety of different non-invasive imaging modalities that play a role in the diagnosis, management, and prognostic assessment of women with IHD. Overall risk assessment and an understanding of the sex-specific differences in the presentation and pathophysiology of ischemia and performance of available diagnostics is imperative when deciding the optimal test for evaluating women for IHD. Female-specific considerations such as exposure of breast tissue to radiation and pregnancy status necessitate a patient-centered approach to diagnosis. Compared with men, women less frequently have obstructive coronary artery disease or undergo coronary angiography and are more likely to have coronary microvascular dysfunction ,23. FiguExercise stress test electrocardiography (ETT) evaluates for inducible ischemia by the presence or absence of ST-segment changes (ST depressions or elevations) along with the assessment of hemodynamic response to exercise and overall cardiorespiratory fitness. Exercise is performed on a treadmill or bicycle ergometry with continuous ECG monitoring. This modality is widely accessible and inexpensive . HoweverStress echocardiography allows for the visualization of abnormal myocardial contractility during exercise when compared to baseline, an indication of inducible myocardial ischemia. Exercise is preferred; however, a pharmacological stress agent such as dobutamine can be used to detect new or worsening left ventricular (LV) regional wall motion abnormalities (RWMA). In addition to the qualitative assessment of myocardial response to stress, quantitative measurements with techniques such as strain rate imaging (SRI) derived from tissue Doppler imaging (TDI) can be employed to assess for myocardial viability. Strain describes the shortening, thickening, and lengthening of the myocardium, which can be used as a measure of regional left ventricular function on echocardiography and can detect characteristic findings suggestive of ischemic myocardium such as reduced peak systolic strain, systolic lengthening, and post-systolic shortening . This reSPECT-myocardial perfusion imaging (MPI) provides information about global and regional LV systolic contractility, LV volume, as well as myocardial perfusion defects during exercise or pharmacological stress for the evaluation of patients with known or suspected CAD. Radionucleotide tracers, most commonly 99m-technetium (Tc99m)-labeled perfusion agents are injected intravenously at peak exercise or following vasodilator administration  or dobutamine administration. Both rest and stress images are typically obtained; however, in selected patients a stress-only protocol may be employed with rest images obtained only if stress images are abnormal . This mop = 0.001). Size and/or severity of perfusion abnormalities significantly decreased for patients receiving maximal treatment and increased for patients undergoing moderate and poor treatment  ..62]. ThiAlthough typically diagnosed by invasive angiography, CCTA may also be of value in the diagnosis and follow-up of SCAD, which affects women in most cases. Typical features of SCAD on CCTA include abrupt luminal stenosis, intramural hematoma, tapered luminal stenosis, dissection and arterial tortuosity . A normaCCTA can provide prognostic data for all-cause mortality and IHD events. Analyses based on the CONFIRM  registry showed a progressive increase in mortality with the extent and severity of CAD  .p < 0.001) and 90-day cumulative  doses, independent of patient characteristics. The lowest nuclear doses employed 1-day Tc-99m protocols (12.2 mSv). The lowest CTA doses were at sites performing ≥500 CTAs/year (6.9 mSv) and with advanced (latest available) CT scanners (5.5 mSv) [Concerns regarding exposure to ionizing radiation with CCTA, specifically to breast tissue in women, have been appropriately raised. However, subgroup analyses of the PROMISE trial compared CCTA and functional testing with regard to safety, incidental findings and effective radiation dose in 9470 patients. CCTA had a similar 90-day cumulative radiation dose compared to functional testing. However, in the subgroup whose physicians intended nuclear stress , CTA had lower median index test  . Breast 5.5 mSv) .Stress CMR can provide accurate assessment of myocardial ischemia, viability, and function. The absence of ionizing radiation with CMR combined with its high contrast and spatial resolution are advantageous, especially in younger or pregnant women. Stress CMR images are obtained with the use of vasodilators  to induce hyperemia followed by a gadolinium-based contrast agent injected peripherally; serial T1-weighted CMR images are then acquired. The contrast enters normally perfused myocardial regions more quickly and in higher concentrations which can be detected as a greater increase in T1-signal relative to abnormally perfused regions . AlthougStress CMR has high diagnostic accuracy owing to its high spatial resolution, ability to differentiate and characterize the layers of the myocardium, and lack of limitation by attenuation artifacts. This high diagnostic accuracy was shown in the MR-IMPACT II  and CE-MARC  trials which enrolled patients with suspected angina to stress CMR and SPECT imaging and compared them to invasive coronary angiography . The CE-A range of effective, non-invasive modalities are available for evaluation of ischemia in women. Exposure of breast tissue to radiation and pregnancy or breastfeeding status are important female-specific considerations which can influence selection. Exercise stress ECG testing can be considered an option in all women regardless of pregnancy status given its safety profile . ExercisPET and SPECT-MPI imaging involve radiation exposure and radiotracer use which are generally contraindicated in pregnancy. The society for nuclear medicine also advises against MPI in women who are breastfeeding but notes that, for those who do receive 99mTc or 13N-ammonia, no interruption to breastfeeding is necessary . The radCMR benefits from lack of radiation exposure and is safe for use in pregnancy, including with the use of gadolinium contrast agents. MRI imaging has not been associated with any mutagenic or teratogenic effects . This moIHD is the leading cause of morbidity and mortality among women. Women with IHD are more likely to present without classic anginal symptoms, face greater diagnostic delay, poorer prognosis and are less likely to be initiated on guideline-directed pharmacotherapy relative to men. INOCA, CMD and SCAD all more frequently affect women compared with men. A variety of noninvasive imaging modalities are available or are emerging for the detection of IHD in women.


Gender-Based Violence (GBV) remains the most challenging and threatening manifestation of gender inequality in Indian society. The outbreak of COVID-19 in India increased the risk of exposure to GBV, often compared to the “shadow pandemic". Girls suffered disproportionally compared to boys during the pandemic -from being pulled out of schools, facing movement restrictions, and being more susceptible to forced marriage and household violence. Pre-existing gender inequalities and regressive gender norms, along with economic instability, also contributed to creating a milieu for violence to thrive. Additionally, the pandemic also challenged GBV service provision and program implementation at the community level. To meet the increasing needs of women and girls during the crisis, national and local civil society organizations attempted to adapt GBV programming and promote innovative approaches to tackle GBV. The secondary review provides insight on the GBV impact due to the COVID-19 pandemic and provides an overview of various challenges at the level of individual, community, institution, and policy. The literature review also highlights strategies adopted to combat GBV in private, public and cyberspace. Gender-Based Violence (GBV) is directed at an individual or group based on actual or perceived biological sex, gender identity, gender expression, or perceived adherence to socially defined norms of masculinity and femininity . WorldwiThe COVID-19 pandemic resulted in a shadow pandemic of violence, i.e., an exponential global increase in GBV. In India, apart from the surfacing of economic and social stress caused by the SARC-CoV-2, it also revealed deep-rooted patriarchy, gender inequalities, and preexisting harmful social norms fueling GBV. The social isolation measures and movement restrictions imposed to prevent the further spread of the pandemic made women and girls more susceptible to violence at the hands of family members, partners, and those living within their homes. Various studies have demonstrated that most GBV cases in emergency conditions are perpetrated by a known individual –9. CompaThe series of lockdowns across the country pushed women from being cut from access to services and information, worsening women's social and economic situation . The priThe maximum of these complaints (36%) was under the right to live with dignity clause, also considered emotional abuse. The pandemic not only had a detrimental impact on the physical and mental health of women and adolescents but also led to an increase in child marriage. From May–July 2020, there was a 33% increase in reports of child marriage to India's first government-operated 24-hour toll-free phone outreach for children . The panGender-specific programming in any area refers to unique programme models and services that address the unique needs of a specific gender group . Due to During the pandemic, the health systems were overwhelmed, leaving women with limited access to the prevention of GBV services. The focus shifted to providing essential services and preventing the spread of COVID-19 –23. The via hotlines for they did not know they existed. It was challenging to ensure the penetration and dissemination of these hotlines in rural areas  into existing maternal and child health services can strengthen the health system's response to GBV. Those providing first-line support must also have access to psychological support. The pandemic highlighted the need to ensure last-mile delivery of essential services and create a robust information-sharing network , 44–46. some key approaches/strategies in three domains- private, public, and cyberspace.Due to the complexity of GBV programming and health facilities prioritizing COVID-19 response, the stakeholders involved in GBV mitigation and treatment adopted private sphere, the organizations have reiterated that the pandemic had further exacerbated intimate partner violence for women who earlier sought the support of friends and family for protection from their partners. With the health and support services being scaled back, the chances of receiving support from the health sector grew rare  reported that the size of the conversation around online violence on Twitter nearly tripled from pre- to during COVID. Urban cities -Bengaluru, Karnataka, Kolkata, Mumbai, and New Delhi, reported exponential growth in interest towards doxing, online stalking, gender trolling, image-based abuse, online sexual harassment, etc. during COVID . Some orA.•There is requirement to change systems and create mechanisms that promote gender-responsive structures and inform decision-makers to ensure linkages across government ministries/departments for a systematic change towards preventing GBV.•Adequate public resources must be allocated for GBV prevention, risk mitigation, and response.•Public planning, budgeting, and financial systems need to integrate gender equality principles and gender analysis .•Development of country/state strategic plans for preparedness and responses need to be adequately guided by gender analysis.•Urgent need to prioritize the coordination of programs and policies across sectors such as health, legal, social welfare, and education to address the composite needs of victims/survivors of GBV.Government and policy makers. •Proportion of existing national legislation to promote gender equality, women and child's rights protection.•Number of active public institutions working towards combating GBV.•Number of public awareness campaigns to raise awareness on GBV, legal rights of women and challenge harmful social norms.•Number of public institutions that maintain gender disaggregated data systems.•Increased number of females in decision-making positions attained through policy intervention.•Number of policies and guidelines placed and effectively implemented to ensure gender concerns are addressed in rescue, relief, rehabilitation, and reconstruction stages of natural disasters or humanitarian emergencies. Potential measurable indicators include:B.•To increase the number of innovative investment opportunities for private or blended capital  related to shifting harmful GBV outcomes.•To promote localization of humanitarian assistance, and support women's and girls' leadership and participation around all areas of program/policy design and implementation.•Removing bottlenecks to ensure funding can reach grassroots organizations working closely with vulnerable communities.•Exploring innovative financing pilots to support localized GBV programming.Donors/Funding Organizations/Philanthropic Foundations.Amount of allocations made to complement Multi Sectoral National Action Plans to address sexual and gender-based violence. •Proportion of funds allocated by international funding organizations investing in prevention, risk mitigation and response towards GBV.•Proportion of innovative models to reduce GBV scaled to impact at local level.•Amount of allocations made to complement multisectoral national /state action plans to address gender-based violence.•Number of active platforms created which amplify voices of women and adolescent girls.•Number of new funding grant opportunities generated to fund gender centric and sustainable solutions. C.•Humanitarian and development organisations should aim at strengthening context-specific partnerships to carry out joined-up regional, country or area-based assessment, planning and programming on GBV.•Awareness-raising materials and approaches should be context-specific, and inclusive in nature depending on local vulnerabilities.•Need to develop innovative approaches for research within in the context of COVID-19 in order to better understand the dimensions of GBV in affected settings.•Usage of data disaggregated by sex, age, and disability, in order to better understand the differential experiences of affected individuals and communities, and to guide gender-informed action in the short, medium and long-term.Civil Society/Humanitarian Organizations.Potential measurable indicators: •Number of gender discriminatory laws, policies and procedures that are amended, enacted, and/or implemented due to advocacy efforts by civil society organizations.•Proportion of community level prevention and response mechanism which are effective and active on the ground.•Number of intersectional analysis undertaken to provide a more comprehensive picture necessary to trigger policy and programmatic shifts. Potential measurable indicators include:Percentage of data sets focussing on how the health and socioeconomic effects of COVID-19 have exacerbating gender-based bias, discrimination, mistreatment, abuse, violence, norms, and the agency of women and girls. •Sexual and gender-based violence report rate, based on the number of incidents of sexual and gender-based violence in a population during a designated time period , expressed as a number of incidents per 10,000 persons during that time period.•Percentage of civil society organizations working towards ensuring accountability of government to respond effectively to gender-based violence. D.•Holistically integrating GBV services  into existing maternal and child health services strengthens the health system's response to GBV.•Providing first-line support must also have access to psychological support.•Provision of adequate training for health workers to handle disclosures of GBV.•Identify support systems that are important for GBV survivors to seek help and stop incidents of violence.•Ensuring last-mile delivery of essential services and creating a robust information-sharing network on GBV.•Potential measurable indicators include:•Proportion of public and private health service delivery points providing empowerment counselling and psycho social support for GBV survivors.•Number of frontline workers/ community service providers trained on gender sensitive delivery standards.•Percentage of clients identified for GBV care who receive post- GBV clinical case based on minimum package.•Percentage of people identified for GBV care who receive first line response (LIVES) according to WHO guidelines.•Number of healthcare professionals capacitated on gender competencies /gender sensitive quality care.•Percentage of providers that demonstrate survivor centred care in GBV screening and first-line response.•Percentage of facilitates that meet the minimum requirements for screening for GBV per WHO guidelines.Service ProvidersGeneratingsex-disaggregated data on impacts of COVID-19 on migrants, covering indicators such as COVID-19 knowledge and behavior, a and social protection or safety nets.The COVID-19 pandemic uncovered the existing gaps in gender programming across the world. Fragmented across sectors, efforts to end violence are sometimes ineffective as they fail to address the intersectional forces that play into GBV. The pandemic also highlighted the need to strengthen accountability and build capacities of local women's organizations to ensure women's voices are heard and amplified. Recognizing the scale and dimensions of GBV within the context of COVID-19, it is imperative that impact and effectiveness of existing and adapted GBV prevention, response, and risk mitigation approaches is reassessed at local, state and national level in India.


Due to favorable antidepressant (AD) efficacy and tolerability, selective-serotonin reuptake inhibitors (SSRIs) are consistently recommended as substances of first choice for the treatment of major depressive disorder (MDD) in international guidelines. However, little is known about the real-world clinical correlates of patients primarily prescribed SSRIs in contrast to those receiving alternative first-line ADs.These secondary analyses are based on a naturalistic, multinational cross-sectional study conducted by the European Group for the Study of Resistant Depression at ten research sites. We compared the socio-demographic and clinical characteristics of 1410 patients with primary MDD, who were either prescribed SSRIs or alternative substances as first-line AD treatment, using chi-squared tests, analyses of covariance, and logistic regression analyses.SSRIs were prescribed in 52.1% of MDD patients who showed lower odds for unemployment, current severity of depressive symptoms, melancholic features, suicidality, as well as current inpatient treatment compared to patients receiving alternative first-line ADs. Furthermore, patients prescribed SSRIs less likely received add-on therapies including AD combination and augmentation with antipsychotics, and exhibited a trend towards higher response rates.A more favorable socio-demographic and clinical profile associated with SSRIs in contrast to alternative first-line ADs may have guided European psychiatrists’ treatment choice for SSRIs, rather than any relevant pharmacological differences in mechanisms of action of the investigated ADs. Our results must be cautiously interpreted in light of predictable biases resulting from the open treatment selection, the possible allocation of less severely ill patients to SSRIs as well as the cross-sectional study design that does not allow to ascertain any causal conclusions. Selective-serotonin reuptake inhibitors (SSRIs) represent a very well studied class of antidepressant (AD) medication that is consistently recommended as the first-line psychopharmacotherapy for major depressive disorder (MDD) in clinical practice guidelines (CPG) throughout the world . AccordiDespite the frequency of SSRIs prescriptions, rather heterogeneous conclusions were drawn in terms of efficacy. While SSRIs, particularly sertraline and escitalopram, were meta-analytically evidenced as gold standard ADs in MDD , other pThe efficacy and acceptability of SSRIs in MDD treatment may be only two of the important aspects influencing treatment choice. In spite of potential adverse effects (AE) that are most frequently related to the gastrointestinal tract and sexual dysfunction , SSRIs wAlthough valuable knowledge on efficacy, tolerability and further important aspects distinguishing SSRIs from other ADs in MDD treatment could be retrieved from randomized-controlled trials (RCTs) and meta-analyses, extrapolation to real-world conditions found in everyday clinical practice is challenging, because of the manifold presentation of MDD which may vary in severity and course and which may include suicidality, psychotic-, melancholic- and atypical features, and/or comorbidities. Therefore, factors that may mediate clinicians’ choices to administer SSRIs over other ADs as first-line ADs in MDD in real-world settings are of interest. To shed light on these aspects, we aimed to illustrate the real-world prescription rates of SSRIs and other AD substances administered as first-line psychopharmacotherapy in 1410 MDD patients from Europe and Israel, and to reveal possible differences in their socio-demographic and clinical patterns.The current analyses refer to the international and multicentric, observational, cross-sectional and non-interventional study with retrospective assessment of treatment response conducted by the European Group for the Study of Resistant Depression (GSRD) . These sAdult in- and outpatients of both sexes were recruited in academic as well as non-academic clinical routine centers in Austria, Belgium, France, Germany, Greece, Italy, Switzerland, and Israel that are mentioned above. In case of interest and eligibility for participation in the present study, all related procedures were thoroughly explained to the patients before signing written informed consent. To be included in the present study, the patients had to be diagnosed with a current single or recurrent major depressive episode (MDE) occurring in the course of MDD as their primary psychiatric diagnosis. Furthermore, they had to undergo an adequate psychopharmacotherapy with at least one AD agent employed in sufficient daily doses and treatment duration of minimally four weeks during the current MDE , 19. TheTo assure a high standard of data quality and inter-rater reliability, exclusively experienced psychiatrists undergoing specific rater trainings were allowed to assess socio-demographic, clinical, and treatment patterns of the enrolled MDD patients who were treated by senior consultants for psychiatry in all recruiting centers. In the course of a comprehensive clinical assessment, medical records of the included MDD patients were considered and the Mini International Neuropsychiatric Interview (MINI)  was applTo determine treatment response patterns based on the GSRD staging model , the MADIn analogy to existing evidence, the current suicidal risk and its extent were ascertained according to the HAM-D item 3 that specifically assesses suicidality , 42. When = 50). Accordingly, the alpha level was set at = 0.001 (0.05/50 = 0.001). Uncorrected p values are displayed in Table α = 0.001). Data were analyzed employing the version 27 of IBM SPSS Statistics.The enrolled 1410 patients suffering from primary MDD  were subn = 734, 52.1%) or other AD substances  including SNRIs (n = 336), noradrenergic-dopamine reuptake inhibitors , NaSSAs (n = 121), serotonin antagonist and reuptake inhibitors , noradrenaline reuptake inhibitors , TCAs (n = 74), monoamine oxidase inhibitors , agomelatine (n = 69), tianeptine (n = 2), and vortioxetine (n = 6) as their first-line AD psychopharmacotherapy during their current MDE. With respect to the individual SSRIs, all six existing substances were distributed in our MDD patients, whereby the majority received escitalopram (n = 257) that was followed by sertraline (n = 163), paroxetine (n = 126), fluoxetine (n = 97), citalopram (n = 71), and fluvoxamine .The socio-demographic and clinical patterns of the whole sample were comprehensively described in our previous reports and are shown in Table p < 0.001). The current occurrence of melancholic features  and suicidal risk . The severity of depressive symptoms measured with the MADRS at onset of the current MDE  as well as at study entry  was lower in this subgroup than in patients receiving alternative agents. While response to the first-line AD treatment occurred more frequently in patients treated with SSRIs (28.5% vs 20.3%), TRD was diagnosed more commonly in patients with alternative first-line AD psychopharmacotherapy  and underwent additional psychotherapy  less frequently than patients treated with other first-line ADs. Psychopharmacotherapeutic augmentation and/or combination strategies in general  and augmentations with at least one antipsychotic (AP) agent , and combination treatment with at least one additional AD  in particular were less commonly prescribed in patients treated with first-line SSRIs as compared to their counterparts.In terms of the administered therapeutic strategies during the current MDE, patients taking SSRIs received a lower mean number of psychopharmacotherapeutics  as well as employment of additional psychotherapy  received SSRIs as their first-line AD treatment during their current MDE, while the remaining group was treated with alternative ADs. Patients receiving SSRIs exhibited a favorable socio-demographic and clinical profile with reduced odds for unemployment and for additional features occurring during the current MDE such as melancholia and suicidality. Furthermore, they also showed reduced odds for current inpatient treatment and for additional therapeutic strategies including combination with other ADs and augmentation with APs. Importantly, patients undergoing first-line AD treatment with SSRIs exhibited a lower severity of depressive symptoms at the onset of the current MDE as well as at study inclusion. A trend towards higher rates of treatment response was observed in patients with SSRIs, while treatment resistance occurred trend-wise more commonly in patients taking alternative first-line ADs.Our findings of preferred first-line treatment with ADs other than SSRIs in melancholic depression, that are in line with available international evidence, may reflect common clinical prescription practice in a severe MDD subtype with specific clinical manifestations and related neurobiological correlates , 52. SpeThe lower proportion of SSRI prescriptions in MDD patients exhibiting current suicide risk is worth mentioning, since suicidality represents a major burden in MDD  that musThe observed lower prescription rates of SSRIs in suicidal MDD patients might as well refer to the fact that suicidality was repeatedly associated with chronicity as well as treatment resistant depression (TRD) and/or difficult-to-treat depression (DTD) , 17, 54 Our further associations between first-line SSRI treatment and a lower severity of depressive symptoms during the current MDE and a lesser need for current and/or previous inpatient treatment support our consensus postulating that a rather favorable disease profile may serve as a possible variable guiding clinicians’ treatment choice towards SSRIs. Another possible reason for the observed prescription rationale may have derived from evidence postulating a varying effectiveness of SSRIs in dependence of the severity of depressive symptoms . ImportaIn terms of treatment outcome, our results revealed a trend towards higher response rates in MDD patients treated with SSRIs as first-line AD treatment, while the prescription of ADs with different modes of action were associated with a trend towards treatment resistance. Being aware of existing international evidence on AD efficacy in MDD favoring alternative AD substances over SSRIs and vice versa , 37, 59 The significantly reduced odds for add-on treatments including AD combinations and augmentation with APs in MDD patients who received SSRIs might represent complementary results highlighting that a further therapeutic escalation is inevitable in case of insufficient response to first-line ADs, that in general affects a considerable number of MDD patients worldwide , 48, 49 Higher rates of unemployment in MDD patients receiving first-line ADs other than SSRIs represented our only significant between-group contrast in terms of socio-demographic aspects and was mostly interpreted in the context of illness severity as well as functional impairment that was more pronounced in our patients with alternative first-line ADs. Precisely, patients showing a lower severity of depressive symptoms as well as less functional impairment may predominantly have been allocated to SSRI first-line medication. The latter assumption might be supported by available international data reporting positive effects of different individual SSRIs and other classes of ADs on workplace functioning .Noteworthy strengths of the present study are the naturalistic design and the large international sample which may best possibly reflect the broad everyday routine. In contrast to the most RCTs, such real-world patient population gathered from in- and outpatient units of university as well as non-academic centers in eight countries allows investigations of heterogeneous clinical manifestations of MDD including suicidality, psychotic features, psychiatric and/or somatic comorbidities, and varying disease course and severity ranging from single to recurrent MDEs with mild, moderate or severe extent of current depressive symptoms. However, potential cross-site differences of the prescription practice, driven by the type of recruiting institution (academic vs. non-academic), divergent insurance situations as well as availabilities and approvals of the specific psychopharmacotherapeutics which might have arisen by recruitments in different European countries, cannot be fully ruled out. To minimize a distortion of our result in these regards, the variable “research center” was accounted for in our statistical analyses. Furthermore, physician-related factors as exact number of years of their experience, which may have influenced treatment patterns and the findings, respectively, were not systematically assessed. To minimize potential biases related to the latter aspects and to assure a high standard of data quality and inter-rater reliability, exclusively experienced psychiatrists undergoing specific rater trainings were allowed to perform the comprehensive clinical assessments of the enrolled MDD patients who were treated by senior consultants for psychiatry in all recruiting centers. Furthermore, the present large multi-site project conducted by the GSRD , 66, 69 Furthermore, the open treatment design may be subject to bias regarding assessment and allocation. The fact that about a half of the included 1410 MDD patients received SSRIs as first-line psychopharmacotherapy and a comparable group of patients was treated with other ADs bears the limitation of relatively small proportions of AD agents that were individually prescribed in the group of patients receiving alternative ADs. This led us not to differentiate between the distinct individual ADs to enable investigations of comparable groups of MDD patients. Similarly, we did not differentiate between the individual SSRIs, which we deem justifiable in light of the fact that superiority of a specific substance could not be demonstrated with certainty and due to the unequal proportion of MDD patients treated with the respective individual SSRIs. While exclusively conventional on-label substances were involved in the current investigation, novel psychopharmacotherapeutic options that have recently been shown to be very effective and, hence, approved in MDD and/or TRD, as esketamine for instance , 49, 65,Most importantly, it has to be pointed out that the cross-sectional design of the study does not allow to ascertain any causal conclusions and, hence, represents an explicit limitation. Clearly acknowledging that this procedure yields less accurate results than prospective investigations, we would like to highlight our treatment outcome measures that were calculated according to the total score reduction between the rMADRS, referring to a time-point when the depressive symptoms reached their maximum , and the cMADRS, representing a time-point of study entry (at least after four weeks of an adequate psychopharmacotherapy). The respective variables reflecting a reduction of depressive symptoms during the current MDE might be, hence, regarded as longitudinal measures providing hints towards causality. We are aware that this approach is inferior to randomized-controlled, prospective conditions; however, in light of the fact that MDD patients were previously shown to adequately recall symptoms for a considerable period of time  and thatThe observed beneficial socio-demographic and clinical profile associated with first-line SSRI administration in contrast to the rather inferior characteristics related to alternative substances may reflect broad adherence of European psychiatrists to the current international treatment algorithms suggesting SSRIs for the initial treatment approach in MDD, while AD substance classes like MAOIs or TCAs are recommended once sufficient treatment response could not be achieved . Further


Pesticides have been used in agriculture, public health programs, and pharmaceuticals for many decades. Though pesticides primarily target pests by affecting their nervous system and causing other lethal effects, these chemical entities also exert toxic effects in inadvertently exposed humans through inhalation or ingestion. Mounting pieces of evidence from cellular, animal, and clinical studies indicate that pesticide-exposed models display metabolite alterations of pathways involved in neurodegenerative diseases. Hence, identifying common key metabolites/metabolic pathways between pesticide-induced metabolic reprogramming and neurodegenerative diseases is necessary to understand the etiology of pesticides in the rise of neurodegenerative disorders. The present review provides an overview of specific metabolic pathways, including tryptophan metabolism, glutathione metabolism, dopamine metabolism, energy metabolism, mitochondrial dysfunction, fatty acids, and lipid metabolism that are specifically altered in response to pesticides. Furthermore, we discuss how these metabolite alterations are linked to the pathogenesis of neurodegenerative diseases and to identify novel biomarkers for targeted therapeutic approaches. With a sharp increase in global life expectancy, the world’s population over 60 years is expected to double from 12 to 22% between 2015 and 2050 WHO . The risAmong the environmental factors, pesticides are one of the many factors linked to the onset of neurodegenerative disorders , organochlorines (OCs), and pyrethroids (PYRs) in biofluids has shown alteration in metabolites related to oxidative stress, inflammatory reactions, and mitochondrial dysfunction  metabolism, enzymes tryptophan 2,3-dioxygenase and the indoleamine 2,3-dioxygenase, metabolizes L-tryptophan into its metabolite L-kynurenine (KYN) , leading to 3-hydroxykynurenine synthesis. Studies on PD indicate that increased 3-hydroxykynurenine levels caused excitotoxicity and increased oxidative stress  levels of tryptophan in PD patients vs. healthy controls, it was determined that tryptophan levels were severely reduced in PD patients  led to an increase in the glutamine levels and metabolism of glutamate, aspartate, and alanine in the brain ; and reduced plasma tyrosine and large neutral amino acids ratio (LNAA)  and reduced glutathione (GSH) systems work together to maintain redox homeostasis. In the event of increased free radicals, GST dimerizes to bind and interact with GSH and reduces the level of free radicals  showed decreased levels of several metabolites, including higher levels of oxidized glutathione  in both the hippocampus and striatum tissue samples . Formamidine pesticides such as chlordimeform (CDM) and their metabolites have been implicated in the inhibition of monoamine oxidase (MAO) , and vesicular monoamine transporter 2 (VMAT2) were reduced , decanoic acid, dihomo-γ-linolenic acid (DGLA), quinic acid, valerenic acid, and 10-hydroxydecanoic acid were noted in PD samples (Willkommen et al. The summary of various pesticides and the selected metabolic pathways affected by their exposure is listed in Table The review summarizes the epidemiological and experimental studies looking for the correlation between metabolites altered by pesticide exposure and their link with neurodegenerative disorders. Reports indicate that less than 10% of PD cases are purely genetics (Simon et al. Neurodegenerative disorders have previously been associated with metabolic abnormalities. Hence, the metabolomic approach is a promising tool that helps identify abnormal metabolite levels and pathways associated with major neurodegenerative diseases (Cai et al. Inflammation-related pathways like tryptophan catabolism, arachidonic acid metabolism, and histidine metabolism, when altered by different pesticides, lead to the accumulation of neurotoxic products driving towards neurodegeneration. Pesticide exposure-induced oxidative stress can cause mitochondrial dysfunction wherein the use of organochlorines and organophosphates has shown alteration of mitochondrial energy metabolism pathways. Mitochondrial dysfunction is often accompanied by oxidative stress and impaired cellular respiration and also leads to apoptosis/autophagy, which is often some of the symptoms of neurodegenerative disorders. Samples from the brain tissue, CSF, serum, blood, saliva, and urine samples all have shown changes in the various metabolite levels. The role of altered dopamine metabolism in Parkinson’s has been well established. Organochlorine pesticides have been shown to affect dopamine metabolism, which could hamper neurotransmission and dopaminergic neuronal survival as a consequence of pesticide resultant oxidative stress. Furthermore, pesticides alter glutathione synthesis and metabolism, further exacerbating the production of reactive oxygen species, thus displaying their role in inducing neurodegenerative disorders. The brain and the activities of the resident neurons are energy driven, meaning they depend on mitochondria for a continuous supply of energy for their abundant activities. The majority of the metabolomic studies have shown that along with mitochondrial dysfunction, the TCA cycle, which is the source of ATP for the cellular activities of these neurons, is impaired due to variations in the metabolite levels within the cycle. Studies show that glycolysis is similarly altered in PD patients, which exhibits another parallel between the pesticide effects and neurodegenerative symptoms. Studies also reveal the alteration of several pro- and anti-inflammatory mediators upon pesticide exposure that are recruited as part of the immediate immune response of the cell. Most importantly, amino acid metabolism, which serves a key role as precursors or intermediates in several overlapping metabolic pathways, like purine and pyrimidine synthesis, neurotransmitter metabolism, citric acid cycle, and urea biosynthesis, is also affected. Altered levels of various amino acids serve as essential early biomarkers for various diseases like Alzheimer’s and PD, although when it comes to human studies, there are several cofactors like the diet that may affect the levels of the metabolites within an individual. However, these pathway changes often culminate in neuronal death, a primary factor for the onset of neurodegenerative diseases.Therefore, this review summarizes the molecular pathways that are vulnerable to chronic pesticide toxicity to understand their physiology, leading to better prediction of pesticide-related health outcomes. Metabolomics data focusing on the nervous system are still scarce though the available evidence supports the existence of specific mechanistic associations between neuronal damage and pesticide exposure leading to neurodegeneration. However, it is also important to validate how the changes in the individual metabolite associated with a particular neurodegenerative phenotype have any measurable influence on the phenotype. A further combined approach of different omics will help better understand the physiological and pathologic processes involved in the human brain.