The coronavirus disease 2019 (COVID-19) pandemic has strained antimicrobial stewardship programs (ASPs) but offered new opportunities. This review summarizes the impact of the COVID-19 pandemic on ASPs, review the contributions ASPs have made in the pandemic response, and highlight the potential role of ASPs in future pandemics. ASPs have been shown to decrease length of stay, antibiotic duration, antibiotic expenditures, rates of Clostridioides difficile infection, and rates of antimicrobial resistance. The coronavirus disease 2019 (COVID-19) pandemic has created unprecedented challenges to the healthcare system, particularly ASPs. To highlight this interconnected relationship, we review the historic role of ASPs as part of pandemic response efforts, how ASPs can and have been leveraged to support the pandemic response, the impact of the COVID-19 pandemic on traditional ASP strategies, and how ASPs can ensure their inclusion as part of future pandemic responses.Antimicrobial stewardship programs (ASPs) work to optimize the use of antimicrobials to improve clinical outcomes, decrease adverse effects of antimicrobials, and lower costs. After implementation of The Joint Commission standard requiring all hospitals to have an ASP in 2017, these programs are now ubiquitous, with 85% of hospitals meeting all of the Centers for Disease Control and Prevention (CDC) recommended ASP core elements in 2018. demonstrated the role ASPs can have in pandemic response during the H1N1 influenza pandemic when their ASP helped create guidelines for the testing, triaging, and treatment of suspected influenza patients. Nevertheless, ASPs do not appear to have been systematically included in pandemic response efforts before the rise of COVID-19. Indeed, the 2017 Society for Healthcare Epidemiology of America Guidance on Outbreak Response and Incident Management does not mention how ASPs can contribute to an outbreak response. In the absence of existing standards or historical experience, most ASPs were either indirectly or not at all involved in the early phases of the COVID-19 pandemic response. Factors that contributed to this blind spot may have included the relatively recent development of antimicrobial stewardship, rarity of global pandemics, limited relationships between ASPs and previously identified pandemic response stakeholders , and limited ASP visibility within individual hospitals and healthcare systems. However, as the pandemic progressed, and particularly as new and repurposed drugs for the prevention and treatment of COVID-19 became available, the potential value of ASPs as part of the pandemic response became increasingly apparent.Ahmad et al To confront these pandemic-related changes, health systems relied on all available resources, including ASPs, which had several features that made them excellent partners for this work.The beginning of the COVID-19 pandemic was marked by tremendous uncertainty, characterized by a lack of information about an emerging pathogen, absence of proven treatment options, shifts in hospital resources and patient volumes, and significant pressures on hospital finances. Health systems rapidly pivoted by increasing critical care volume to meet demand, canceling elective surgeries, shifting personnel, and moving patient visits to telehealth when possible.First, ASPs are increasingly common. ASPs are now required across hospital settings as a condition of participation for the Centers for Medicare and Medicaid Services and for accreditation by The Joint Commission. Therefore, there was a critical mass of stewards that could be leveraged when the pandemic arose. Second, because most members of ASPs have subspecialty training or experience in infectious diseases (ID), they have content expertise that can be utilized as part of the response to emerging pathogens. Third, ASPs have unique skill sets, including prescription audit and feedback, guideline implementation, medication supply management, and investigational drug procurement, that can help support the work of overburdened frontline providers. Fourth, as the pandemic progressed, the importance of clear and consistent messaging about what was and was not known about COVID-19 became increasingly evident. ASPs have historically leveraged behavioral psychology and communication skills to assist stewardship efforts and can be used to facilitate critical messaging related to the rapidly changing knowledge about COVID-19. Lastly, because their work cuts across entire healthcare systems, ASPs are likely to have diverse personal and professional networks.These relationships are also likely to include teams that are critically important to pandemic response, including the microbiology/virology laboratory and IPC. Furthermore, because the stewardship community is relatively small, there are interinstitutional relationships that facilitate collaboration and learning based on the experience at other centers. Shortages of swabs used for respiratory pathogen panels and Staphylococcus aureus PCRs also occurred, so ASP teams encouraged use of culture-based methods of detection to ensure appropriate work up of infections continued to occur. Personal protective equipment (PPE) was also in short supply; healthcare workers needing to don new PPE every time they entered a patient’s room. ASPs worked to reduce healthcare worker room entries and PPE needs by consolidating and adjusting timing of medication administrations, converting therapy from IV to PO to decrease length of stay, and decreasing unnecessary vancomycin monitoring.ASPs have made many important contributions to the COVID-19 pandemic response, including the management and mitigation of supply shortages. At the start of the pandemic, COVID-19 laboratory tests were not widely available and frequently had a long turnaround time. Kubin et al created a COVID-19–specific alert in the EHR to notify their ASP team when a patient was severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PCR positive and when they were on specific medications, such as hydroxychloroquine. This alert system allowed the ASP team to improve patient safety by identifying patients on hydroxychloroquine who had prolonged QT intervals and patients receiving remdesivir without appropriate laboratory monitoring . Similarly, 2 other ASPs utilized flags and other EHR tools to identify which COVID-19 patients would most benefit from ID consultation, a resource that became increasingly strained as hospital censuses rapidly increased.Electronic health records (EHR) have been increasingly leveraged by ASP teams to support stewardship activities and the COVID-19 pandemic has seen a number of ASPs use them for pandemic response.The severe morbidity and mortality seen in COVID-19 patients prompted an unprecedented use of antimicrobial agents, both within and outside clinical trials. Given the initial limited supply of medications thought to show antiviral activity against SARS-CoV-2 and uncertainty around which patients would benefit the most from their use, ASP teams applied their expertise to the development of COVID-19 therapeutic guidelines, and they helped allocate these limited resources.For example, our own ASP created guidelines for anti–COVID-19 monoclonal antibody treatment at a time when our hospital was only receiving a handful of doses each week. These guidelines helped ensure that these treatments went to the patients who would most benefit as opposed to those that had the easiest access. In addition to COVID-19–specific therapeutics, ASPs worked to mitigate against the surge in antibiotic prescribing in COVID-19 patients that occurred despite evidence that bacterial coinfection and secondary infections were rare. utilized a smartphone application that had been developed as a repository for institution-specific antimicrobial guidelines to disseminate COVID-19–related content to their medical center. At the time of their publication, these guidelines were downloaded by >3,000 people and individual pages were accessed >200,000 times. Most impressively, the information on the smartphone application was updated >90 times to keep providers abreast of the most current information. Although Pierce et al were unable to quantify the clinical impact of this intervention, the work highlights how existing ASP tools can be repurposed as part of the pandemic response.Another challenge of the COVID-19 pandemic response was collating and disseminating the rapidly accumulating knowledge about SARS-CoV-2 and the care of COVID-19 patients. Pierce et al One of the first opportunities for ASP involvement in IPC efforts was early case identification of COVID-19 patients. Both ASPs and IPCs rely on data collection with help from IT departments; the pandemic highlighted an opportunity for collaboration in acquiring and analyzing these data. ASPs and IPCs were able to work together on COVID-19 guidelines, ensuring consistent messaging during an evolving pandemic. Notably, opportunities for ASP and IPC collaboration exist for infections beyond SARS-CoV-2. A survey from Tomczyk et al highlighted the difficulties that the COVID-19 pandemic placed on antimicrobial resistance surveillance worldwide. More than half of the 73 countries of the WHO Antimicrobial Resistance (AMR) Surveillance and Quality Assessment Collaborating Centres Network surveyed reported decreased ability to work on AMR projects, decreased number of surveillance cultures, and decreased availability of nursing staff and reagents needed for laboratory testing. In the future, it will be even more important for ASP and IPC programs to work together to tackle AMR problems that have been exacerbated by the COVID-19 pandemic.The challenges of the COVID-19 pandemic have led to increased collaboration, best exemplified by the partnership between ASPs and IPC programs. The rationale for ASP and IPC collaboration, including shared infrastructure, related need for senior hospital leadership support, similar multidisciplinary team structure, shared need for information technology (IT) support, and linked outcome metrics, have been well summarized by Assi et al. Nori et al argued that while ASP programs have not traditionally been involved in vaccine management, they are well positioned to assist in this process. ASP team members are frequently on pharmacy and therapeutic committees, have experience in the allocation of new and novel drugs, have pharmacy experts knowledgeable about drug transport and storage, have experience with coordinating with multiple different arms of the healthcare system, and are trusted leaders for information dissemination. Indeed, in a survey of 51 ASP leads, >90% reported that they were involved in the allocation of COVID-19 vaccines, which often required significant effort from the already strained ASPs. Further opportunities to improve vaccine uptake, including non–COVID-19 vaccines, are highlighted by the work of Shallal et al who demonstrated significant missed opportunities for vaccination against Streptococcus pneumoniae and influenza during the COVID-19 pandemic.Prevention of infection is one of the best ways to decrease antimicrobial use, and vaccines are among the most powerful tools to accomplish this. Not only can vaccines protect an individual patient, and society at large, against infectious threats, vaccines can also be an important tool in society’s response to AMR. Collins et al highlighted the importance of pharmacy care in their retrospective review of 197 patients with COVID-19 who had at least 1 pharmacist intervention during their hospital stay. These 197 patients had 15,818 medication days and received 1,572 pharmacist interventions (mean medication interventions per patient 8). Of these interventions, the most common were regimen simplification and medication timing to minimize the frequency of hospital staff room entry while caring for infected patients, followed by stewardship interventions to ensure optimal use of antimicrobials. More recently, with the authorization of new oral COVID-19 antiviral medications like ritonavir-boosted nirmatrelvir, pharmacists have again been of great importance in counseling, performing medication reconciliation, and mitigating potentially severe drug–drug interactions.The COVID-19 pandemic has seen recognition of the remarkable work done by ID and critical care physicians, nurses, and other healthcare providers. However, we must acknowledge the specific challenges faced and the contributions of pharmacists to the pandemic response. Despite increased work responsibilities and work reassignments, pharmacists helped monitor COVID-19 medication use and adverse effects, helped manage drug shortages and supply chain issues, worked to preserve PPE, helped establish temporary COVID-19 hospitals during surges, wrote treatment guidelines, and provided education to clinicians and the public. The surge in antibiotic utilization for COVID-19 patients and barriers to in-person interaction between ASPs and medical teams were additional challenges to successful stewardship. Vaughn et al distributed a survey to 51 ASP leads to assess how the role of ASPs changed during the pandemic. ASPs reported a median of 5 new duties and 82% reported an increase in work load. These additional duties included development of COVID-19 treatment guidelines, allocation of anti–COVID-19 medications, COVID-19 education to healthcare providers and the public, and isolation and PPE guidelines. Worryingly, only 8% of ASP leads reported increased full-time equivalent (FTE) support to deal with these new responsibilities and 18% reported decreased FTE. Also, 73% of respondents reported a decreased ability to perform normal stewardship activities and 71% had symptoms suggestive of burnout. Similarly, in a survey of 95 ASP leaders in the United Kingdom performed by Ashiru-Oredope et al, 64% of respondents reported that COVID-19 had a negative impact on ASP activities, including stewardship ward rounds, antimicrobial audits, and quality improvement interventions. Pandemic-related challenges have also decreased self-reported effectiveness of ASP teams, with respondents of one survey reporting reduced adherence to ASP recommendations, increased use and duration of broad spectrum antibiotics, and decreased screening for multidrug-resistant organisms.Some authors have postulated that the increased focus on COVID-19 by ASPs could lead to decreased efforts towards non–COVID-19–related ASP targets, potentially leading to suboptimal antimicrobial prescribing. These units were often staffed by internal providers outside their normal care area, such as pediatric providers pulled to take care of adult patients, or by traveling clinicians who were less familiar with institution-specific antibiograms, guidelines, and stewardship strategies. Consequently, compliance with existing stewardship practices may have decreased and suboptimal antimicrobial prescribing may have increased, although these trends have not been systematically studied. The sheer volume of critically ill and dying patients during the early phases of the pandemic may have also affected the success of antimicrobial stewardship interventions.In response to patient-volume surges, hospitals frequently created new COVID-19 units to increase their critical-care capacity. Although the increased use of technology with stewardship comes with its own challenges, benefits such as increased efficiency for stewards and increased accessibility have been noted. Furthermore, work on high-visibility projects, such as vaccine response coordination, may help build relationships with hospital administration, while multidisciplinary work, for example on monoclonal antibody efforts, helps establish new and strengthen existing relationships with hospital colleagues. With this enhanced visibility, there is an opportunity for ASPs to highlight the impact of their work and credibly advocate for increased resources and protected time.Despite the numerous challenges, it is also important to acknowledge the potential benefits of the pandemic to ASPs. Published data suggest that the pandemic accelerated use of technology as part of some ASPs. Pediatric health systems and ASPs have had to deal with similar challenges as adult providers, such as lack of effective treatment options early in the pandemic. However, pediatric ASPs faced several unique challenges.Although much of the COVID-19 pandemic focus has been on adults, children have also been severely affected. The CDC estimates >1,200 pediatric deaths in the United States due to COVID-19 since the pandemic began. Despite the existence of several high-risk groups of children who might benefit from these therapies, the relatively low number of children compared to adults made hiring dedicated staff less practical and the burden of providing access to these medications often fell on pediatric ASPs.As part of the pandemic response, many institutions and public health offices focused on adult care were able to hire dedicated staff or set up stand-alone infusion centers for COVID-19 monoclonal antibodies to manage the overwhelming patient volume. Children <12 years of age were an even greater challenge because they were not covered under initial EUAs, and pediatric ASPs were frequently called upon to help navigate the time-consuming process of obtaining compassionate use of these drugs through expanded access programs, which took time away from traditional ASP activities. Given the adult-oriented focus of the pandemic, initial supplies of COVID-19 monoclonal antibodies available to pediatric institutions were often limited, and ASPs were frequently called upon to help identify patients who might benefit the most from these treatments.Early in the pandemic response, clinical trials identified a number of treatment modalities including remdesivir, dexamethasone, and COVID-19 monoclonal antibodies; unfortunately, children were excluded from these trials. This created several challenges. Although initial emergency use authorizations (EUAs) often included children 12 years of age and older, no pediatric data were available to guide the use of these investigational agents in adolescents, and pediatricians were forced to extrapolate potential risks and benefits of treatment from adult studies. Therefore, pediatric ASPs collaborated to evaluate risks and benefits of use of investigational drugs in adolescents and young children and created guideline documents. Similarly to COVID-19 monoclonal antibodies, supplies of these vaccines were limited early in the pandemic, and the prioritization of higher risk adult patients forced ASPs to stratify pediatric patients risk based on limited data. In addition, pharmacists faced unique patient safety challenges with multiple vaccine formulations and doses approved for a single vaccine manufacturer, requiring additional logistical management to prevent vaccine dosing and administration errors in children.Like the aforementioned treatments, COVID-19 vaccines greatly influenced the management of the pandemic. Here again children were excluded from initial trials and approval. To date, >2 years into the pandemic, only 1 COVID-19 vaccine is available to children in the United States, and it is only authorized for children aged >5 years. The COVID-19 pandemic has proven just how quickly our existing healthcare systems can become overwhelmed by novel pathogens. As discussed earlier, ASPs have expertise, skill sets, and experience that can help assist hospital administrators, healthcare epidemiologists, and frontline healthcare personnel as they respond to these threats. To ensure that ASPs are able to meaningfully contribute, they must be integrated early on as part of the pandemic response. This inclusion will ensure clear lines of communication between ASPs and other key stakeholders and allows for early identification of additional resources that may be necessary to ensure success . For their part, ASPs are encouraged to think broadly and creatively about the scope of their work and engagement. For example, ASPs are encouraged to include all members of the healthcare system, as part of their work. Cortenay et al describe potential benefits of using nurses in ASP projects, including nurses’ frequent experience with collaboration and presence at bedside, which could help in distinguishing between viral and bacterial infections as well as identifying patients who may be appropriate for transition from IV to enteral antibiotic therapy. In addition, nurses’ frequent bedside contact is ideal for patient communication and engagement around the appropriate use of antimicrobials. Future collaboration between nursing and ASP may be beneficial, but programs will need to ensure that they are not placing increased burden on already overtaxed nurses. ASPs used their expertise in rational antimicrobial use to assist in allocation when anti–COVID-19 medications, such as remdesivir and COVID-19 monoclonal antibodies, were scarce. In the future, ASPs can consider extending these skills to vaccines and nontraditional antimicrobials such as convalescent plasma. Importantly, ASPs should prioritize the collection of data related to their pandemic response work so that those in charge of resourcing programs understand the breadth and depth of work that is happening. Disseminating generalizable knowledge to the medical community through publication is important as well.ASPs have been greatly impacted by the ongoing COVID-19 pandemic, but they have also been invaluable contributors to the pandemic response. Despite no mention of ASPs in previous pandemic guidance, we and others believe that ASPs should be part of future pandemic planning.In conclusion, ASPs around the world have stepped up to aid in the COVID-19 pandemic response. In addition to continuing their daily activities to protect patients from the adverse effects of antimicrobials and help slow the spread of antimicrobial resistance, ASPs have shaped many aspects of the pandemic response. ASPs worked to identify patients with COVID-19, and ensure they received appropriate treatment, all while helping health systems manage scare resources. There were both significant benefits to ASPs and significant costs of this pandemic-related work. In the future, ASPs should be considered part of a comprehensive pandemic response, but it will be important to ensure they are adequately resourced to do so.


Bone is a metabolically active organ that undergoes regular and ongoing remodeling throughout the lifespan, which is crucial for the maintenance of mineral metabolism and normal skeletal structure . The dynOsteogenic differentiation is the key process in bone formation, and the decreased osteogenic differentiation ability of mesenchymal stem cells (MSCs) leads to decreased bone formation, which has been proven to be responsible for multiple bone disorders, including osteonecrosis of the femoral head and osteoporosis. Multiple clinical trials and animal experiments have demonstrated the beneficial effects of MSCs in preventing bone loss . Thus, MLin et al. found that polydatin (POL) may have a promising therapeutic effect in osteoporosis by bioinformatic analyses, and POL treatment exhibited an increase in the ALP-positive area, the alizarin red-positive area and levels of osteogenic gens, including collagen type I alpha 1 (COL1A1), alkaline phospatase (ALP), osteocalcin (OCN) and Runx2, through MAPK signaling pathway in vitroLin et al., 2021 Another studies supplemented that POL could improve osteogenic differentiation of MSCs potentially via BMP2-Wnt/β-catenin signaling pathway  into osteoblasts and osteoblast matrix mineralization, but inhibited osteoclast formation and function in a dose-dependent manner, and subsequently reversed estrogen deficiency-induced bone loss. AQX-1125 is first-in-class, oral SHIP1 activator in clinic, and a clinical trial regarding the effect of the SHIP1 activator AQX-1125 reported that it was well tolerated and low side effect (e effect . TherefoHao et al.; A combination of biophysical stimuli and drugs therapy may be a future direction in treatment osteoporosis. Given the inefficiency of current biomaterials and bioactive molecules, biophysical stimulation for MSCs osteogenesis, including internal structural stimulation, external mechanical stimulation and electromagnetic stimulation, showed promising potential to prevent and treat osteoporosis, although specific osteoinductive mechanisms remains unclear (In summary, the Research Topic indicated that the efficacy of these therapies and its mechanism against osteoporosis, highlighting the fact that strategies for enhanced osteogenic differentiation of MSCs in osteoporosis are effective. As researchers come round to the understanding that bone is a mechanosensitive tissue, biophysical stimulations offer some unique advantages for enhancing osteogenic differentiation of MSCs. Furthermore, drugs therapy in combination with biophysical stimuli may be as a first line therapy in the future. We predict that this Research Topic will continue to rapidly evolve and attract more researches to develop more antiosteoporosis therapies with few side effects.


Atherosclerotic cardiovascular disease is a growing threat among cancer patients. Not surprisingly, cancer-targeting therapies have been linked to metabolic dysregulation including changes in local and systemic lipid metabolism. Thus, tumor development and cancer therapeutics are intimately linked to cholesterol metabolism and may be a driver of increased cardiovascular morbidity and mortality in this population. Chemotherapeutic agents affect lipid metabolism through diverse mechanisms. In this review, we highlight the mechanistic and clinical evidence linking commonly used cytotoxic therapies with cholesterol metabolism and potential opportunities to limit atherosclerotic risk in this patient population. Better understanding of the link between atherosclerosis, cancer therapy, and cholesterol metabolism may inform optimal lipid therapy for cancer patients and mitigate cardiovascular disease burden. Dysregulation in lipid signaling is a critical factor for development of atherosclerotic cardiovascular disease (ASCVD). Heightened appreciation for the “causal” association between low density lipoprotein (LDL) levels and ASCVD inspired new paradigms for cardiovascular risk mitigation including stringent emphasis on lipid lowering therapies and a “lower is better” approach for risk reduction , 2. HoweWhile the cardiotoxic effects of cancer therapeutics, particularly cytotoxic therapies, remain a growing area of research, the direct study of the interweaving of cancer biology, cancer therapeutics, and pathophysiology of ASCVD is less common. Cancer and ASCVD share similar risk factors such as age, tobacco use, and diabetes. However, even after controlling for these risk factors, there is still a strong association between cancer and ASCVD and data indicates that those with a personal history of cancer have 3.42 higher odds of having an elevated ASCVD risk score , 9. Likede novo in the liver. Thus, the liver acts as a master regulator of systemic cholesterol levels and is involved in intricate crosstalk with other metabolically active organs and peripheral tissues to maintain cholesterol homeostasis. Cholesterol biosynthesis requires the coordinated activity of multiple intracellular proteins including the rate limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). The liver also regulates the uptake of LDL by regulating the activity of the LDL receptor (LDLR). Both HMGCR and the LDLR are regulated by sterol regulatory element binding transcription factor 2 (SREBP2), which translocates to the nucleus in response to low endoplasmic reticulum cholesterol content to enhance lipid uptake and biogenesis , 1615, 1ogenesis . The Livogenesis . A key gogenesis . Thus, Logenesis . These pA portion of the increased ASCVD risk seen after cancer diagnosis is driven by shared risk factors that predispose to both ASCVD and cancer, such as diabetes mellitus, obesity, and metabolic syndrome . HoweverAs survival among cancer patients improves, the increased risk of death from ASCVD is magnified . For exavia topoisomerase II inhibition, mitochondrial impairment, and generation of reactive oxygen species that result in inhibition of DNA and RNA synthesis , it is difficult to assess their unique impact on e et al.  showed te et al. , 35, 40.via significant decreases in lipid levels, C-reactive protein, and hepatic and other enzymes, suggesting that multiple pathways are involved in the atherosclerotic and vasculo-toxic effects of imatinib (via different target receptors may have opposing or synergistic effects.Tyrosine kinase inhibitors (TKIs) are a mainstay of therapy for gastrointestinal, genitourinary, hematologic, and lung cancers. They are a diverse class of agents targeting various kinases involved in pathways related to tumor angiogenesis. The off-target effects of TKIs can impact lipid metabolism or promote cardiotoxic side effects. Imatinib, a first-generation TKI targeting BCR-ABL1, reduces cytoplasmic phosphorylation of LDL receptor related protein, a key component of LDL signaling that is involved in activating lysosomal enzymes, glucose-induced insulin secretion, and cholesterol metabolism. For example, in a study of rabbits fed a high cholesterol diet, imatinib therapy reduced cholesterol levels and the toxic effects produced by hyperlipidemia in the aorta and liver. These effects were mediated imatinib . Other Timatinib , while TTKIs are a key therapeutic agent in chronic myelogenous leukemia (CML) . Since iAs a class, BCR-ABL1 TKIs have been found to have varying toxic effects, including adverse events that may be lipid-independent, such as vascular toxicity, cardiotoxicity, and pulmonary hypertension . Among vStudies to date on TKI therapy suggest that imatinib may have an atheroprotective effect, while other TKIs may have a more deleterious effect. Ponatinib targets a gatekeeper mutation in the BCR-ABL protein, T3151, that confers resistance to other TKIs among CML patients, but after approval was noted to be linked to myocardial infarction or stroke in 24–48% of patients . One stuCompared to imatinib, nilotinib, and dasatinib have shown greater affinity for the BCR-ABL1 tyrosine kinase protein and thus more effective BCR-ABL1 inhibition, largely replacing imatinib as first line therapy for CML . In smalLipid-modulating effects of the more novel TKIs used in gastrointestinal, genitourinary, and lung malignancies are still being elucidated. In a study of 299 patients with lung cancer, patients treated with gefitinib (an EGFR TKI) had lower TC levels after 30 days of treatment . LorlatiThe mechanistic Target of Rapamycin (mTOR) signaling pathway is involved in regulation of gene transcription and protein synthesis related to cell proliferation and immune cell differentiation . Primariin vitro exposure of human hepatocytes to cyclophosphamide did not affect metabolic pathways involved in lipogenesis  such as tamoxifen have a protective effect against ASCVD and dyslipidemia . SERMs aIn a metanalysis of RCTs with variable follow up intervals, tamoxifen reduced cardiovascular events by 25–35% compared to placebo . In largAromatase inhibitors (AI) reduce circulating estrogen by reducing production of the hormone . CompareAndrogen deprivation therapy (ADT) using hormonal treatment such as gonadotropin-releasing hormone antagonism, or less commonly, bilateral orchiectomy, is a standard component of treatment of advanced prostate cancer . The typDue to high cell growth rates, ovarian follicles are exquisitely sensitive to chemotherapy . IncidenCancer treatment in the recent era is most often multimodality, and non-chemotherapy treatment agents affect dyslipidemia and ASCVD risk. Radiation therapy, often used in conjunction with chemotherapy therapy regimens, is an independent risk factor in the development of ASCVD . ExplosiStudies of the effects of immunotherapy on lipid metabolism are limited. Chimeric antigen receptor-T cells and Bispecific T cell Engager therapy are growing areas of immunotherapy, particularly for hematologic malignancies, but their effects on lipid metabolism are unknown. Immune checkpoint inhibitors (ICIs) are an increasingly common therapy for a variety of cancers and known to have multiple cardiometabolic toxicities , 128. ICHematopoetic stem cell transplant (SCT) patients are at elevated risk of hypertension and diabetes, and further evidence suggests that SCT is an established accelerator of atherosclerosis . A retroin vitro study, human bronchial epithelial cells were exposed to radiation doses known to cause cell dysfunction in humans  has been shown to promote the development of atherosclerosis in affected tissues . Radiatin humans . Increasn breast  and prosn breast  cancer pThe identification of effects of CHIP adds a new dimension to the interweaving of the cardiovascular and cancer biology spheres. CHIP mutations create a hematologic pre-malignant state that can progress to hematologic malignancies such as leukemia, lymphoma, and myeloma at a rate of 0.5–1% per year . HoweverThe effect of cancer and cancer therapy on atherosclerosis suggests that cancer patients are at higher risk of ASCVD-related morbidity and mortality, necessitating greater attention on prophylaxis and treatment of cardiovascular disease in this population. A recent review article by Zullig et al. summarizes the evidence regarding pharmacologic and non-pharmacologic management of cardiometabolic comorbidities in cancer survivors . StatinsStatins may benefit oncology patients through their cholesterol-lowering effects as well as an anti-cancer effect. For example, the use of statins prior to cancer diagnosis has been linked to reduced risk of developing certain cancers such as pancreatic cancer and non-Hodgkin lymphoma –148. AddPCSK-9 inhibitors are an established alternative or adjunct therapy to statins for cholesterol reduction. They have profound LDL-lowering effects that have been shown to reduce cardiovascular events , 155. ThNon-pharmacologic approaches to lipid-lowering in cancer patients are also important. Exercise oncology is a growing area of interest to promote health and longevity among cancer survivors . TailoreThus, there is promising data to suggest that cancer patients with dyslipidemia may benefit from traditional treatment with statins or PCSK-9 inhibitors. The next frontier for clinicians and researchers is identification of more nuanced treatment guidelines for cardiooncology patients who may be at increased risk of atherosclerotic events. Further research into the changes in lipid metabolism attributable to various cancers and cytotoxic therapies is needed to inform such guidelines.Screening for ASCVD in the general population relies on traditional risk stratification tools, however, such tools do not often account for a history of cancer or cancer treatment. In adults who received cancer treatment as a child, the Childhood Cancer Survivor Cardiovascular Risk Calculator can estimate risk based on age, gender, and prior treatment . HoweverWhile studies are underway to better characterize the increased ASCVD risk that cancer patients carry, clinicians treating the cancer patient should be aware of classes of cytotoxic therapy that are known to increase risk in long-term dyslipidemia. These include Anthracyclines, VEGF inhibitors, and ADT. Clinicians should consider more aggressive screening of cardiovascular risk factors in patients who have received or are receiving treatment with these agents. Additionally, clinicians should utilize the diagnostic tests used in cancer management to help risk stratify ASCVD risk. For example, coronary artery calcifications on chest imaging are associated with clinically significant ASCVD , 171. MoStatin therapy should continue to be the mainstay of lipid lowering therapy in cancer patients and clinicians ought to consider lower thresholds of traditional ASCVD risk calculators to initiate or intensify therapy in cancer patients treated with chemotherapy associated with dyslipidemia or ASCVD, chest radiation, immunotherapy, or stem-cell therapy . At thisAlthough the present review focuses on cytotoxic effects related to cholesterol, other related lipids have been implicated in cancer risk. Oxysterols are derivatives of cholesterol that act as direct activators of the nuclear receptor LXR . LXR actDyslipidemia is a crucial factor in the development of ASCVD. The increased incidence of ASCVD in cancer patients suggests the need for greater attention on prophylaxis and treatment of cardiovascular disease in this population, including study of potential precursors of both disease states, such as CHIP. Future research may include specific study of various cytotoxic therapies on incident ASCVD, as research to date suggests that these effects may be variable. Prospective studies are needed to assess dyslipidemia and the risk of ASCVD after each class and combination of chemotherapy treatment to better predict the likelihood of an ASCVD event in cancer survivors . MoreoveRB, ND, EY, and TS: envisioning, design, writing, and revision of the manuscript. All authors contributed to the article and approved the submitted version.TS receives research funding from the National Institutes of Health , American Heart Association, and Burroughs Welcome Fund outside of the present study. EY receives research funding from CSL Behring, Boehringer Ingelheim, and Eli Lilly outside of the present study.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Autism spectrum disorders are common neurodevelopmental disorders that are defined by core behavioral symptoms but have diverse genetic and environmental risk factors. Despite its etiological heterogeneity, several unifying theories of autism have been proposed, including a central role for cerebellar dysfunction. The cerebellum follows a protracted course of development that culminates in an exquisitely crafted brain structure containing over half of the neurons in the entire brain densely packed into a highly organized structure. Through its complex network of connections with cortical and subcortical brain regions, the cerebellum acts as a sensorimotor regulator and affects changes in executive and limbic processing. In this review, we summarize the structural, functional, and genetic contributions of the cerebellum to autism. Autism spectrum disorders (ASD) are a group of phenotypically and genetically heterogeneous neurodevelopmental disorders that are diagnosed by core deficits in social communication and the presence of repetitive, stereotyped behaviors . IndividMounting evidence has implicated the cerebellum in ASD due its central role in regulating sensorimotor functions –7. HowevAutism is now diagnosed early in childhood, often prompted by delayed milestones . Thus, aHere we discuss how abnormalities in the cerebellum of individuals diagnosed with ASD may give rise to clinical features. We consider altered cytoarchitectural findings, subcortical and cortical projections, and gene expression patterns in the cerebellum of individuals with ASD. We examine how these findings interplay with the excitatory/inhibitory imbalance hypothesis of autism.In humans, cerebellar development begins in the embryonic period, continues through the fetal period, and completes its volumetric growth arc after about a decade of postnatal life ,14. Two The resultant mature cerebellar circuit has a repeated, uniform cytoarchitecture. As shown in Molecular layer interneurons (MILs), which include basket and stellate cells, are the main inhibitors of PCs. PCs are the only output of the cerebellar cortex  and primUnveiled in convergent evidence from diffusion tensor imaging, functional magnetic resonance imaging, and lesion-based symptom mapping, the cerebellum has many higher-order sensory, motor, cognitive, and limbic connections. The simplified circuit diagram depicted in Both neuroimaging and histopathological studies have documented atypical structure and functional connectivity of the cerebellum that correlate findings with severity of ASD symptoms. Hypoplasia of the posterior cerebellar vermis with an enlarged cisterna magna was first described in a 21-year-old man diagnosed with autism without intellectual disability . SubsequFurther age-dependent trends in ASD can be found in lobular volumes in structural MRI studies, with findings often limited to certain younger age groups ,60. BroaAdditional functional connectivity studies have also found atypical lateralization patterns, including reduced lateralization to the left cerebral and right cerebellar hemispheres and vermes in ASD during language processing and production ,62. AlthFunctional connectivity studies have detected noncanonical activity in cerebrocerebellar networks related to social interaction and language in adolescents with ASD. This is evident in multiple domains: global cerebellar increases in connectivity , increasFurther increases in neurotypically out-of-network cerebellocortical functional activity have also been identified in ASD. Findings include overconnectivity between cerebellar cortex and ipsilateral cerebral regions in a manner that falls outside of topographical principles of cerebellar organization, as contralateral cerebellocerebral connections are much more common in neurotypical individuals ,64. ThisHigher excitation to inhibition (E/I) ratios have been extensively reported in the cerebral cortex of individuals with autism –78. RobuThe cerebellum’s vast connective network to large-scale cortical and subcortical networks could serve to propagate massive excitatory imbalances throughout the brain and is vastly affected by alterations in PCs in autism. The role of the PC is to integrate multiple time-sensitive, complex inputs from throughout the cerebellar cortex, create appropriately-timed simple ,85 and cConvergent lines of evidence have repeatedly documented alterations in PCs in ASD. Studies of human postmortem cerebellum from individuals with ASD detected reductions in PC size, density, and expression of the GABAergic precursor, glutamate decarboxylase 65 (GAD65) and GAD67 ,76,88,89These PC-specific alterations are coupled with other known cerebellocortical neuronal circuit abnormalities that may further exacerbate E/I imbalances and ASD symptomology. This includes the retention of, on average, four CF inputs per PC whereas neurotypical cerebella retain only a single CF afferent per PC . In neurPC afferents may be further altered in ASD. Their loss likely occurs after the development of cerebellar MLIs in ASD, as proper migration of basket and stellate cells rely upon PC signaling, and no cytoarchitectural MLI abnormalities—density of MLIs or proportion of MLI to PCs—have been found based on sampling right Crus II in ASD . HoweverUltimately, this reduction in GABAergic transmission and reports of glutamatergic alterations ,99 . ThConvergent evidence across multiple studies and modalities demonstrates structural and functional impact to the cerebellum in ASD. Precise mapping between macroscopic and microscopic differences in the cerebellum with clinical features and subdomains of ASD is still emerging. Transcriptomic, histological, and functional studies converge on Purkinje cell dysfunction in ASD, but many of the other neuronal and non-neuronal cell types of the cerebellum have not been studied in ASD and require investigation. ASD-specific impairments in cerebellar function are reciprocally connected to impaired cerebral cortex function. Thus, the next frontier requires coordinating studies to disentangle the complex interplay between the cerebrum and the cerebellum in ASD.Supplementary Table S1


The heart is a functional syncytium controlled by a delicate and sophisticated balance ensured by the tight coordination of its several cell subpopulations. Accordingly, cardiomyocytes together with the surrounding microenvironment participate in the heart tissue homeostasis. In the right atrium, the sinoatrial nodal cells regulate the cardiac impulse propagation through cardiomyocytes, thus ensuring the maintenance of the electric network in the heart tissue. Notably, the central nervous system (CNS) modulates the cardiac rhythm through the two limbs of the autonomic nervous system (ANS): the parasympathetic and sympathetic compartments. The autonomic nervous system exerts non-voluntary effects on different peripheral organs. The main neuromodulator of the Sympathetic Nervous System (SNS) is norepinephrine, while the principal neurotransmitter of the Parasympathetic Nervous System (PNS) is acetylcholine. Through these two main neurohormones, the ANS can gradually regulate cardiac, vascular, visceral, and glandular functions by turning on one of its two branches (adrenergic and/or cholinergic), which exert opposite effects on targeted organs. Besides these neuromodulators, the cardiac nervous system is ruled by specific neuropeptides (neurotrophic factors) that help to preserve innervation homeostasis through the myocardial layers (from epicardium to endocardium). Interestingly, the dysregulation of this neuro-signaling pathway may expose the cardiac tissue to severe disorders of different etiology and nature. Specifically, a maladaptive remodeling of the cardiac nervous system may culminate in a progressive loss of neurotrophins, thus leading to severe myocardial denervation, as observed in different cardiometabolic and neurodegenerative diseases . This review analyzes the current knowledge on the pathophysiological processes involved in cardiac nervous system impairment from the perspectives of both cardiac disorders and a widely diffused and devastating neurodegenerative disorder, Alzheimer’s disease, proposing a relationship between neurodegeneration, loss of neurotrophic factors, and cardiac nervous system impairment. This overview is conducive to a more comprehensive understanding of the process of cardiac neuro-signaling dysfunction, while bringing to light potential therapeutic scenarios to correct or delay the adverse cardiovascular remodeling, thus improving the cardiac prognosis and quality of life in patients with heart or neurodegenerative disorders. The sinoatrial node, in the wall of the heart’s right atrium, is the independent cardiac pacemaker; it originates the cardiac impulse, whose diffusion through cardiomyocytes is allowed by their tight junctions, forming a functional syncytium. The central nervous system regulates the cardiac rhythm, modulating its speed through the two branches of the autonomic nervous system: the sympathetic system, which exerts its function through norepinephrine , and the cholinergic system, whose neuromodulator is acetylcholine (ACh). In addition, the cardiac innervation undergoes a characteristic regulation by neuro-signaling: small neuroactive molecules (neurotrophins) contribute to producing an innervation gradient through the membranes of the myocardium (epicardium to endocardium). The impairment of this neurochemical pathway occurs in different cardiometabolic and neurodegenerative disorders and may cause dysfunction in heart rhythm, leading to severe denervation or sudden cardiac death (SCD), as shown in myocardial infarction, heart failure, and possibly, Alzheimer’s disease (AD). Here, we explore the physiological and molecular mechanisms involved in the alterations of the heart neuronal network observed both in cardiac and neurodegenerative illnesses and we propose therapeutic solutions for cardiac pathologies with a recognized imbalance in the two components of the autonomic system responsible for cardiac remodeling.2+), which produces inotropic positive effects; enhanced potassium currents (K+) (The control of cardiac activity is  directlynts (K+) , which mNorepinephrine also provokes a vasoconstriction effect, triggering the α-1 receptors  on vascuin vivo model, this local control of cardiac electrical activity is altered, accompanied by a higher difference in myocardial repolarization and impaired activation propagation  involved in cardiovascular regulation are located in the intermediolateral cell column (IML) of the lateral horn and gray commissure along T1–L2 spinal levels. The SPNs between T1–4 are essential for cardiac sympathetic modulation . Postganpagation .Along this line, the adrenergic nervous system’s adverse remodeling has been well characterized in different cardiovascular disorders  . MoreoveThe intrinsic cardiac nervous system (ICNS) is characterized by clusters of ganglia known as ganglionated plexi, localized in epicardial fat pads . These gThe cardiac plexus is situated at the base of the heart and is composed of a combination of cardiac nerves and small parasympathetic ganglia. Among these ganglia, the most important is the Wrisberg ganglion, located between the tracheal bifurcation and the pulmonary artery division. In addition, other small intrinsic parasympathetic ganglia are in the cardiac atrial wall. From the cardiac plexus, some nerve fibers run along the right coronary artery, left coronary artery, and their branches, reaching the heart. Other fibers penetrate the sinoatrial and atrioventricular node, or project to the thicker vascular walls in the atrial and ventricular myocardium. Stimulation of the vagus motor nucleus reduces both heart rate and myocardial contraction with a similar effect upon pressure. The vagus nerve is the 10th and longest cranial nerve, which provides an indispensable brain-body connection that modulates essential aspects of autonomic physiology like heart rate, breathing, blood pressure, gut motility, reflexes, and vital behavior . Vagal aNotably, vagotomy (subdiaphragmatic) and vagus nerve electrical stimulation (VNS) seem to represent a potential therapeutic strategy in different clinical conditions, albeit some clinical concerns still remain to be addressed. Understanding vagal sensory activity may open new therapeutic horizons, turning on or off specific afferent endings, thus modulating the function of the autonomic nervous system. Of note, cardiac neurons of the PNS are located in the dorsal motor nucleus of the vagus (DMV) nerve, and the nucleus ambiguous in the medulla oblongata. Cholinergic preganglionic neurons project through the vagus and glossopharyngeal nerves, synapsing with postganglionic cells that in turn synapse onto the heart. Therefore, unlike sympathetic neurons, cardiac parasympathetic fibers are anatomically independent of the spinal cord . The choNew scientific insights  demonstrConversely, extracardiac signals of the sympathetic and parasympathetic nervous system interplay with a complex network of intrinsic cardiac neurons involved in the epicardial neural plexus formation . NotablyOf note, besides the autonomic reflexes, ANS homeostasis is modulated by a sophisticated and well-organized cardiovascular neurohormonal axis. Notably, stress-sensitive baroreceptors (mechanoreceptors) are located in both high-pressure arterial (aortic arch and carotid sinus) and low-pressure venous networks . Central and peripheral chemoreceptors, present in the brainstem, carotid sinus, and aortic arch respectively, detect the modifications in arterial oxygen and carbon dioxide concentration. Lastly, polymodal receptors located in the walls of the cardiac chambers, respond to both mechanical and chemical inputs and stimulate sympathetic nervous system outputs in the setting of receptor activity desensitization . In addivitro tests and animal models , brain-derived neurotrophic factor (BDNF) , neurotrGFLs play a key role in many biological processes including cell survival, neuritogenesis, cell differentiation, and cell migration. These neuropeptides perform their activities through GDNF family receptor-α (GFRα) receptors, particularly GFRα1, and a receptor tyrosine kinase (RET receptor) encoded by the RET proto-oncogene. The signaling complex involves a member of the GFRα protein family (GFR1α) and RET. The activation of the first one induces the initial GFL-GFRα receptor complex formation, then the complex enrolls two molecules of RET, triggering trans-autophosphorylation of specific tyrosine residues within the tyrosine kinase domain of each RET molecule; phosphorylation of these tyrosines promotes intracellular signal transduction processes.The cardiac autonomic system  also undDifferent reports  have shoOther studies have demonstrated a sophisticated crosstalk between endothelin-1 (ET-1)  and NGF:Cardiovascular disorders represent the predominant cause of death worldwide, together with metabolic alterations and neurodegenerative disorders such as Alzheimer’s disease. Clinical studies show that a cardiac nervous system  derangemAtrial fibrillation (AF)  is the m- paroxysmal atrial fibrillation  ;- persistent AF, which requires a pharmacological or electrical approach for its arrest, usually longer than 7 days.- long-standing persistent AF, lasting more than 1 year when adopting a rhythm control strategy.- permanent AF , when itThe diagnosis occurs with electrocardiography analysis detecting the loss of “P” waves on the isoelectric line and the irregularity of R- R cycles. A specific classification of AF , based oThe electrical dysfunction is characterized by a “storming electrical impulse” with alteration of cardiac rhythm  and perfMore recent electrophysiological reports  and ther2+ accumulation, sarcolemma reduction, and glycogen accumulation), responsible for atrial physiological and structural abnormalities.The persistence of AF induces cellular and subcellular modifications  receptors using epicardial resiniferatoxin . Thus, tThe shift from adrenergic to parasympathetic phenotype is also sustained by glycoprotein 130 receptors that allow the “cholinergic dress acquisition” of adrenergic neurons. Supporting a transitory cholinergic trans-differentiation in adrenergic cardiac neurons, after gp130 receptor deletion, parasympathetic genes were not expressed post- MI. Thus, transient sympathetic co-secretion of norepinephrine and acetylcholine may favor a strong reaction mediated by inflammatory cytokines , inducinNeuronal remodeling reaches its final phase with the development of heart failure , a complThe pathophysiological basis of HF is constituted by a blood pressure decrease, which triggers a “reaction flow”; the cardiac output lowering is detected by carotid sinus receptors  that senThe extensive activity of the endocrine system and adrenergic circuits promotes a bulky augmentation of phlogistic cytokines  , secreteThe entire process develops in a severe disruption of cardiac sympathetic fibers . AccordiFrom myocardial infarction to heart failure development, neurons in the adrenergic ganglia show an overlap between cholinergic and adrenergic markers and gradually promote the synthesis of parasympathetic modulators , mediateAD is a complex neurodegenerative disorder and the main form of dementia, characterized by a progressive accumulation of cerebral parenchymal β-Amyloid (Aβ) plaques and intraneuronal tau neurofibrillary tangles, associated with widespread brain inflammatory processes. The disease induces a gradual cognitive decline with progressive memory dysfunction . AlthougAge is the main risk factor for both AD and HF , and theLi and others have identified interesting missense mutations in PSEN1 (Asp333Gly) and PSEN2 (Ser130Leu) genes observed in AD patients affected by HF . In lineBesides synaptic, neuroimmune, and vascular dysfunction, AD is accompanied by a significant impairment in neurotrophic signalling, with a progressive loss of the two main neuromodulators, NGF and BDNF . SpecifiIn line with our hypothesis of a link between heart and brain dysfunction, recent clinical investigations, as well as studies in animal models, have highlighted the beneficial effects promoted by different cardioprotective drugs  inhibitors, sartans, and Aldosterone receptor antagonists) in Alzheimer’s disease and cognitive dementia. The cardioprotective drugs, in addition to providing preventive effects , also apThe sustained adrenergic hyperactivity described in post-MI models represents a compensatory organic strategy to counteract the blood pressure reduction. However, this initial mechanism only represents a transitory solution, because the continuous and robust sympathetic response leads to congestive heart failure . During The higher NE circulating levels encourage β-ARs binding and the consequent cardiac fibers hypersprouting, which results in remodeling of the cardiac autonomic system, the main recognized cause of ventricular hyperinnervation and tachyarrhythmia . ConcurrIn this context, our Review analyzes current therapies to prevent and neutralize heart failure and their possible roles in reverting the cardiac neuronal maladaptive remodeling .The roles of beta-blocker therapy on cardiac sympathetic remodeling have been observed also in animal models. The inflammatory process developed during MI and extended in HF involves different cytokines, especially the powerful peptide angiotensin- II, produced following the RAAS  circuit ESC Guidelines identify beta-blockers as the first pharmacological solution to contrast HF  and the Many studies  analyzedPatients with HF on beta-inhibitors treatment have shown a reverse in ventricular derangement, as shown by an improvement of cardiac MIBG re-uptake . DespiteAngiotensin Converting Enzyme inhibitors reduce the activity of the ACE, which is responsible for the conversion of Angiotensin- I (AT- I) -produced as a result of different reactions between a liver compound  and a kidney hormone - in the peptidic marker AT- II. Therefore, ACE inhibitors stop the inflammatory consequences and decrease norepinephrine, inducing remodeling of the cardiac fibers network and restoring cardiac performance. Moreover, RAAS dysfunction induces hyperproduction of the cortical adrenal mineral corticoid hormone “aldosterone”, whose function is to retain sodium in organic fluids, increasing the systolic ventricular tension and thereby causing hypertension. ACE inhibitors represent an important pharmacological treatment for cardiac output hypertension. Similarly, angiotensin receptor antagonists (ATRs), also called sartans, play a crucial role in the management of hypertension and HF . These dHardwick and colleagues have studied the implications of the ACE inhibitor captopril on cardiac plexus remodeling triggered during MI in a guinea pig model . NotablyRenin inhibitor agents, such as aliskiren, represent another important resource in HF treatment: acting on the RAAS system, this drug prevents the conversion of angiotensinogen to angiotensin I.In a rat model, Kasama and others have analyzed the contribution of spironolactone on the recovery of cardiac performance after heart injuries, in a heterogeneous population of 30 patients affected by HF . They obAnother study , has poiThe autonomic nervous system remodeling is one of the common factors involved in the etiopathological mechanisms of cardiovascular disorders, including cardiac arrhythmias, MI, and HF. Despite the advances in the medical and surgical fields, the progression of cardiac illnesses is still growing, together with the mortality rate . NotablyAdrenergic renal afferent and efferent fibers participate in the maintenance of cardiovascular homeostasis, counteracting stress stimuli that occur in cardiac injuries. Specifically, the renal sympathetic network is involved in the modulation of blood pressure, heart rate, and cardiac output . In chroEarly experimental studies demonstrated the antihypertensive effect mediated by renal denervation in animal models with nephrectomy or metabolic syndrome . Renal dhttps://clinicaltrials.gov/ct2/show/NCT01392196. Accessed 1 March 2015 (RSD4CHF), Available at: https://www.clinicaltrials.gov/ct2/show/NCT017 90906. Accessed 1 March 2015). These randomized trials demonstrated the safety and efficacy of renal sympathetic denervation as a well-tolerated treatment to delay the progression of chronic HF, effectively reducing all-cause mortality. Renal denervation significantly decreased LV hypertrophic maladaptive remodeling in patients with resistant hypertension, thus allowing the use of renal denervation also in the HF population with preserved LV ejection fraction  . Renal denervation showed important beneficial effects in the modulation of numerous comorbidities involved in the stimulation of the sympathetic system and liable for the exacerbation of HF pathological mechanisms, such as glucose tolerance, insulin levels, and HOMA indices in hypertensive patients affected by metabolic disorders , associated with a reduction in mortality risk in severely hypertensive patients . After nEF ≥50%) . The antEF ≥50%) . Of inteEF ≥50%) . Similarisorders , associaisorders . In addiisorders . Albeit Experimental evidence highlighted the efficacy and beneficial effects mediated by VNS as a novel approach for the treatment of several cardiovascular diseases . Specifip < 0.05), although no difference was appreciated in LV end-systolic volume measurements (p = 0.49)  .The contrasting results that emerged in these clinical trials may be related to heterogeneity in the HF population and VNS protocol applied . HoweverThe development of specific biomarkers to monitor the effects of VNS on cholinergic tone, adrenergic hyperactivity, and control the impaired afferent system, will allow to determine whether vagal neurostimulation has clinical advantages over approved therapies.Based on this rich body of evidence, we postulate that innovative therapeutic approaches are needed to promote the reparative mechanisms in the heart after injury, facilitate the restoration of the autonomic nervous system, and preserve neurotrophic signaling pathway homeostasis in the brain/heart axis. In this regard, more research is needed to dissect the physiological role played by ANS stimulation and neurotrophins in the heart tissue. This new knowledge will positively impact both neurodegenerative disorders as well as different cardiovascular diseases. Indeed, neuromodulation approaches could represent a key solution to counteract the cardiac nervous system remodeling, which leads to the severe myocardial denervation and lethal cardiac disorders . Although the application of neurotrophins in cardiovascular diseases is still debated and technical concerns have been raised about their administration, parallel findings demonstrate the key role played by NTFs in the modulation of the brain/heart axis, with possible preventive value. Since cardiovascular disease is known to increase AD/dementia risk and pathology , the proAchieving a better understanding of the poorly described role of the cardiovascular neuro-signaling pathway and the ANS in both heart disorders and dementias, while expanding our knowledge of the disease mechanisms, will allow the development of novel biomarkers and therapeutic strategies to correct or delay the adverse cardiovascular remodeling, improving the prognosis, pathology and quality of life in patients with heart disease, AD, or different types of dementias.


Leadless left bundle branch area pacing (LBBAP) represents the merger of two rapidly progressing areas in the field of cardiac resynchronisation therapy (CRT). It combines the attractive concepts of pacing the native conduction system to allow more physiological activation of the myocardium than conventional biventricular pacing, with the potential added benefits of avoiding long-term complications associated with transvenous leads via leadless left ventricular endocardial pacing. This perspective article will first review the evidence for the efficacy of leadless pacing in CRT. We then summarise the procedural steps and pilot data for leadless LBBAP, followed by a discussion of the safety and efficacy of this novel technique. Finally, we will examine how further mechanistic evidence may shed light to which patients may benefit most from leadless LBBAP, and how improvements in current experience and technology could promote widespread uptake and expand current clinical indications. Cardiac Resynchronisation Therapy (CRT) is a well-established treatment for symptomatic dyssynchronous heart failure . ConventHowever, despite widespread uptake and success, studies consistently demonstrate that over 30% of implanted patients fail to derive benefit from conventional CRT . SeveralSeveral studies have reported favourable acute outcomes with LV endocardial pacing. . Endocarin-situ capable of producing continuous right ventricular (RV) pacing, which can be either a conventional device, such as a pacemaker or implantable cardioverter defibrillator (ICD), or a leadless RV pacing device such as MICRATM . The transmitter and battery detect an RV pacing pulse emitted by the co-implant. Within 10 ms of detection of the RV pacing stimulus, the transmitter emits a number of ultrasound pulses to locate the receiver electrode. Once the transmitter is electronically optimally aligned, a longer ultrasound wave is emitted, which is detected and converted to a pacing stimulus by the receiver electrode. This results in LV pacing, and thereby BiV pacing. Observational . In the presence of LBBB or complete heart block, high output temporary HBP from the right side may generate a LBP. If this fails, RV pacing can be used to map a retrograde LBP. A steerable sheath, such as the Medtronic FlexCath Advances LBBAP, , key queWiSE-CRT implantation is an invasive procedure which is performed in a co-morbid population with very few alternative treatment options, and carries an increased risk profile compared to standard CRT implantation. A systematic review and meta-analysis of studies to date  reportedWith regards to safety, an area which is particularly pertinent to leadless LBBAP is the transition from a retrograde aortic technique to a trans-septal technique. A meta-analysis of 181 patients revealed a femoral arterial vascular access complication rate of 5% . The traThe efficacy of leadless CRT using the WiSE-CRT system has been reported in several observational studies . A meta-p < 0.05).The technique for leadless LV septal endocardial pacing targeting the LBBA was first described by Elliott et al.  The authWhilst leadless septal pacing targeting a LBP has been performed using the WiSE-CRT system , whetherLeadless LBBAP is an exciting new technology which combines the fields of CSP and leadless CRT to provide treatment for a challenging and high-risk group of patients with heart failure. In the short term, improved operator experience will promote more widespread uptake. Refinements to this novel implantation technique will improve safety, success rate, streamline workflow, and reduce parameters such as procedure duration and fluoroscopy time.in vivo data, where acute haemodynamic improvements have been noted with AVD optimisation in both lead-based HBP (in vivo mechanistic studies are needed to clarify the biventricular activation pattern achieved with leadless LBBAP, whether there is significant dyssynchrony, and whether there are adequate programming algorithms to overcome this effectively in the WiSE-CRT setting.Questions remain regarding several areas of leadless LBBAP related to efficacy and patient selection, which will determine its eventual utility amongst all available CRT modalities. Initially, EAM studies are needed to determine whether LV septal WiSE-CRT implantation targeting the LBP achieves conduction system capture, as is postulated by current limited data . Such stased HBP  and LBBAased HBP  to allowAnother area of interest is which patients are most likely to benefit from leadless LBBAP. The CRT population is heterogenous, comprising various conduction disease phenotypes and cardiomyopathy aetiologies, often with complex left-sided electrical activation patterns. How LBBAP performs in the presence of these factors, both in the lead-based and leadless settings, remains unclear.in vivo. In part, this is because the presence of septal scar creates technical difficulty in placing a pacing lead to the LBBA with the standard technique of deep interventricular septal deployment (It is well established from studies of conventional CRT that pacing in areas of scar is predictive of poor response . This phployment . Leadlesin vivo studies corroborate the in-silico data, it is possible that measurement of conduction velocity could be used peri-procedurally within standard WiSE-CRT implantation workflow to guide a decision on whether a LBBAP or lateral wall implant is performed.A related area is the effect of His-Purkinje and myocardial conduction velocity on outcomes of CSP. With regards to long-term directions for leadless LBBAP, its place in the field of CRT will ultimately be determined by future clinical trials testing its safety and efficacy compared to conventional CRT and lateral wall endocardial pacing. Further improvements in the leadless technology, such as longer battery life and the ability to LV pace without an associated co-implant, are also in progress. If these developments come to fruition, there is potential for the expansion of indications for leadless LBBAP to become a first-line CRT modality in selected patients.


Timor-Leste faces many challenges implementing quality maternal, newborn andchild health (MNCH) services due to resource constraints and socio-culturalfactors that disproportionately affect the health of women and children. Ascoping review was conducted to map the quality of MNCH services against WHOquality standards on: 1. Provision of care, 2. Experiences of care, and 3.Cross-cutting standards. The literature search identified 1058 citations, fromwhich 28 full-text articles met the inclusion criteria. The findings highlighthealth workers’ limited capacity to provide quality services and referrals. Themajor reasons for this are: a lack of essential supplies, poor infrastructureand transport, limited opportunities for ongoing learning, and gaps in healthinformation systems. Provision of care standards and cross-cutting standardsrequire attention at a broad systems level. Findings related to experiences ofcare highlight the importance of effective communication, respect, and emotionalsupport, particularly for vulnerable women and children who have difficultyaccessing services, and for those who have experienced violence. Theseexperience-related standards could be addressed at an individual health workerand health service level, as well as at a systems level. This review providesdirection to focus quality-improvement initiatives within local healthfacilities, as well as at municipal and national level. The goal outlines specific targets including, to reduce maternal, neonatal,and child mortality (by 2030), to ensure universal access to sexual and reproductivehealth care services, and to achieve universal health coverage (UHC). All thesetargets require the coordination and delivery of quality health services withinaccountable health systems. Health systems that have the capacity to measure and usedata to improve services. Despite substantial progress during the era of the Millennium DevelopmentGoals (MDGs), inadequate resources remain a significant challenge to achieving the SDGs. In regions such as Sub-Saharan Africa and Southern Asia lack of access toquality health care and extreme poverty are major contributory factors to high ratesof maternal, neonatal, and child mortality.5Health care for women and children has been an important focus of the SustainableDevelopment Goals (SDGs). This focus is encapsulated in goal number 3: “Ensurehealthy lives and promote well-being for all at all ages.”7 These frameworks identifystandards vital to achieving quality improvement, including: 1. Evidence-basedpractices for routine care and management of complications; 2. Actionableinformation systems; 3. Functional referral systems; 4. Effective communication; 5.Respect and preservation of dignity; 6. Emotional support; 7. Competent, motivatedhuman resources, and 8. Availability of essential physical resources. The first 3standards reflect “provision of care,” the next 3 the “experience of care” and thelast 2 address cross-cutting factors which are pre-requisite standards for providingboth the provision and experience of care standards.7The World Health Organization (WHO) has widely advocated for improvements in thequality of maternal, newborn, and child health. It has established frameworks andstandards for improving the quality of maternal and newborn care, and that ofchildren and adolescents, in health facilities.810 A task mademore challenging when resource limitations are combined with ongoing political andsocial conflict.12 Timor-Leste is a post-conflict country situated between SouthEast Asia, Australia and the Pacific; it is the newest nation in Asia. Independencefrom Indonesia was achieved in 2002 after years of occupation. Substantial progress has been made to rebuild the health care systemfollowing Indonesian forces exit from the country, however major challenges remainto achieve health and wellbeing for the nation’s most vulnerable. The 72% of Timor-Leste’s population live in rural and remote areas and 42%live below the poverty line.16 The pregnancy-relatedmortality ratio is 218 deaths per 100 000 live births and infant and under-5mortality rates are 30 and 41 deaths per 1000 live births, respectively.16 Maternal andchild health services are provided by a multidisciplinary cadre of health workersincluding doctors, nurses, and midwives. Delivering quality and accessible maternal, newborn, and child health (MNCH)care remains a priority focus for the Government of Timor-Leste and its developmentpartners.Providing quality health services has proved difficult in low- and middle-incomecountries.The aim of this review is to search the literature on MNCH service delivery inTimor-Leste and to map factors affecting quality of care based on WHO qualitystandards. The review offers a framework for stakeholders who want to improve thequality of care in Timor-Leste, and provides a baseline analysis for designing MNCHquality improvement initiatives linked to WHO evidence-based standards.18 The review focused onarticles published within 5 years prior to commencement of the study in 2018.This review was undertaken as part of a larger study on quality improvement of MNCHservices in Timor-Leste. A scoping review methodology was chosen to assess theextent of the literature and to explore factors affecting the quality of MNCHservices in Timor-Leste. Arksey and O’Malley’s framework was used to guide thereview using the following steps: 1. Identifying the research question, 2.Identifying relevant studies, 3. Study selection, 4. Charting the data, and 5.Collating, summarizing and reporting the results.There were 2 main research questions:What quality oriented MNCH literature exists in the context ofTimor-Leste?To what extent do the retrieved articles address the recent WHO qualitystandards?We accessed 7 electronic databases: MEDLINE, Ovid Emcare, Cochrane Library,Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO,Informit, and Scopus. Gray literature sources, including Google Scholar, Google, andOne Search, were searched for additional articles relevant to the topic. A targetedsearch of the Timor-Leste government website was performed via Google to elicit anypublicly available government documents or other gray literature.The search strategy used the following MeSH subject headings: “Quality improvement”OR “Patient-centered care” AND “Maternal health” OR “Child health” AND“Timor-Leste.”The inclusion criteria were:Published literatureUnpublished gray literatureBetween 2014 and 2018Written in EnglishTimor-Leste contextRelevant to MNCH service deliveryThe exclusion criteria were:Articles outside of year rangeLanguages other than EnglishGlobal or regional reports with minimal Timor-Leste contentArticles with context outside of MNCHArticles that could not be linked to any areas of WHO quality improvementframework describe a 2-staged screening process utilizing the PRISMA framework. Oneauthor (MK) assessed the retrieved articles against the inclusion and exclusioncriteria. Ambiguous articles were resolved by consensus amongst the co-authors. Asub-sample was then checked by the second author (DL) for accuracy.Tricco et alThrough title screening, articles were excluded that did not relate to quality ofhealth care or MNCH in Timor-Leste. When abstract screening, the keywords “Quality,”“Timor,” “Maternal,” and “Child” were used to assess eligibility. In cases wherethese words were not identified in an abstract the full text was searched. Articlesthat described Timor-Leste within a global context or with other countries wereincluded only if they provided a sufficient level of information related toTimor-Leste. While screening full texts, articles were further investigated toassess whether they could inform 1 or more of the WHO quality standards.The literature search yielded 1058 articles which, after removal of duplicates, wasreduced to 481. Four hundred fifteen publications were excluded after title andabstract review because they did not meet the criteria for publication year,Timor-Leste setting, MNCH topic or were assessed as not relevant. Sixty-six fulltext publications were screened and a further 38 articles excluded because they didnot provide relevant information related to any of the WHO quality standards, orbecause they were multi-country publications that mentioned Timor-Leste but did notprovide detailed, country-specific information. Thus, the screening yielded 28articles for inclusion in the scoping review .A data extraction table for charting study characteristics, key findings, andrelationship with WHO quality standards was developed by the authors throughconsensus. The extraction table consisted of columns to record information on theauthor, year of publication, objective, study design/type of report, location/studycontext, sample/participants, article findings, and relationship to WHO qualitystandards .Data weThe findings from the retrieved articles were mapped against each domain of the WHOquality standards to provide a narrative overview of existing literature related toeach of the themes. A basic description of the number of articles that fell intoeach domain was included to provide an overview of the extent and distribution ofthe studies.The findings section is presented according to the WHO quality of care standards: 1.Provision of care standards, 2. Experience of care standards, and 3. Cross-cuttingstandards. A total of 28 articles were included in the review, many of the articlescovered multiple standards. Nineteen articles were related to provision of care, 25articles were related to experience of care, and 24 articles addressed cross-cuttingstandards .The provision of care domain covers 3 elements: a. Evidence-based care practicesfor routine care and management of complications, b. Referral, and c. Datamanagement. The review findings on this domain are summarized below.2022infectious diseases,23immunization,24 antenatalcare,2427 andchild health services.29 One report cites theinadequate capacity of health workers, limited availability or stock-outs ofcommodities, and delayed care-seeking, as challenges to implementation ofnutritional interventions within antenatal and postnatal care services in Timor-Leste. Another article suggests that women will seek health care from afacility when they have confidence in the health care provider, which relieson the provider following evidence-based guidelines.The findings indicate the importance of service providers adhering toclinical protocols in managing nutrition interventions,31 One article contendedthat high numbers of referrals to tertiary hospitals were due to low skilllevels of health care providers in community settings . Another study described the management of postpartum hemorrhage (PPH)by paramedics while transporting patients to a higher-level facility, usingthe Timor-Leste National Ambulance Service. The retrospective audits found paramedics diagnosed 85% of cases, butdid not regularly use resources available to them such as oxygen andintravenous isotonic crystalloid fluid. This study illustrates how referralsystems are linked to other provision of care standards such as the routinemanagement of complications.A functional referral system manages referral cases according to protocols.Rapid transportation to higher-level facilities is used when required. Threearticles identified poor road conditions in Timor-Leste as posingdifficulties for referral transportation.33 According to 1 study,more than 60% of death data was found to be missing or incomplete intertiary hospital settings.The review identified gaps in information systems, highlighting improperrecord keeping practices, missing records, and a scarcity of data,particularly with regard to maternal health, child health, andvaccinations.34 The 3elements covered are: a. Effective communication, b. Respect and preservation ofdignity, and c. Emotional support. All these elements are critical in thepost-conflict social landscape of Timor-Leste. Several articles in theliterature review highlight experience of care through the concept ofpatient-centered care, a model that prioritizes the needs and rights of theperson receiving care and puts them at the center of decisions that affectthem.The experience of care standards refer to the experiences of clients at the pointof care.313543 Two articlesrecommend antenatal counseling by skilled providers, a provision that canimpact women’s decision-making during labor and childbirth and influencebreastfeeding practices.37 Midwives play animportant role in the communication of information to women both in-personand by using mobile phone technology. One article describes the implementation of Liga Inan (ConnectingMothers), an mHealth program designed to promote communication betweenmidwives and pregnant women using mobile phone messaging. Women described the usefulness of the service, which providedinformation on healthy behaviors and reminded them when they had anappointment at a health facility. Having access to a mobile phone helpedwomen receive health information and increased their understanding of healthcare services. One study found a link between mobile phone ownership andincreased use of maternal and newborn health services, however afteradjusting for socioeconomic factors, mobile phone ownership was notindependently associated with service use.The review identified 14 articles that addressed the theme of “communication”to facilitate healthcare delivery and improve the experiences of pregnantwomen and their children. Health providers can play a critical role in addressing the issue ofIPV through sensitive communication with women about their needs, and byproviding advice on how they can best be assisted to safety.Intimate partner violence (IPV) is common in Timor-Leste. Women who haveexperienced such violence exhibit higher rates of sexually transmittedinfection, low birthweight births, and pregnancy termination than thegeneral population. They have lower attendance at antenatal clinics and areat greater risk of morbidity and mortality. depression, and adult separation anxiety (ASA) have been observed in women, especially married women, during theirpregnancy and postnatal period. If IPV and mental health issues are not addressed there could besignificant consequences for women and children’s physical and mentalhealth. In one study, midwives emphasized that, in addition to sensitivecommunication, women require health system factors like patient privacy andsuitable appointment lengths to be in place so that they can talk openlyabout their problems.Explosive anger, One Government report emphasized women’s lack of knowledge about howto access health care services, indicating the need for broadercommunication with communities and outreach by health services. The article also highlights the role of educational campaigns inimproving people’s understanding of child health issues. For example,Servisu Integrado du Saude Comunidade (SISCa), an Integrated CommunityHealth Service Program introduced by the Ministry of Health, serves as anawareness building platform for the prevention of diseases.In a global consultation forum poor communication was reported as a barrierto the delivery of quality healthcare services.3944Health providers’ empathy, confidentiality and communication skills, as wellas referral of women to appropriate services, play a critical role inincreasing patient safety and preservation of dignity.Respect and dignity are an essential element of quality of care. Articlesfrom the literature search related to this domain were mostly focused on theneeds of women who have a history of trauma and violence.39One article found that a quarter of study participants were subjected toIPV, which was associated with cultural obligations and bride price stress. Midwives providing health services to women acknowledged the fearfelt by women speaking out about the violence they face. The midwives recognize the importance of kindness and emotionalsupport when providing counseling and discussing treatment options withthese women.Similar to the need to show respect and preservation of dignity, women whohave experienced trauma need significant emotional support. A study performed in Rivers State, Nigeria found that more than 50% ofprimary health care workers wanted to move away from their current place of work. Similarly, rural retention has been identified as a problem in a policyanalysis in Bangladesh.Cross-cutting standards include competent and motivated human resources, and theavailability of essential physical resources. Available human and physicalresources were the key challenges identified in this review. Inadequateavailability of skilled providers, especially in rural settings, has been a keyconstraint in Timor-Leste since independence.4951 Twogovernment reports focus on interventions to do with human resources andidentify increasing the number of skilled-birth attendants (SBAs) as apriority program area for MNCH services.33 Two articleshighlight Timor-Leste’s health workforce crisis within the Asia Pacificregion and focus on insufficient number of SBAs.49 The latter articlealso highlights low worker population density and low expenditure on healthservices as factors that contributed to high maternal mortality in Timor-Leste.A critical element in delivering quality health care is a skilled workforce,identified in the WHO quality standards as a “competent motivated humanresource.” Fourteen articles in the literature search included issuesrelated to human resources for health in Timor-Leste. Another article stresses that skilled health care workers arerequired to deliver quality health care services to children The limited skills of midwives was described as a challenge in 1article, which found inconsistent practices in the management of post-partumhemorrhage (PPH) when transporting women to health facilities.One article reports additional challenges in providing skilled nutritioninterventions to women and children when there is a scarcity of supplies andcommodities, or when the women arrive late for care. Quality antenatal care provision requires the employment of skilledmaternal health workers however, less than half (45%) of women received therecommended 4 antenatal visits. One report described Timor-Leste’s achievement in integrating the 10Steps to Successful Breastfeeding into national quality standards for MNCH. Two articles describe the shortage of health care workers as acritical issue, especially in rural areas.51 Midwives are the coreproviders managing pregnant women and children in health care facilities andare often required to handle sensitive cases of pregnancy-related violenceand/or mental health issues. They are therefore a central component of the health workforceproviding healthcare services to women and children.The 2016 Timor-Leste Demographic and Health Survey reported that only 57% ofbirths were assisted by skilled health care workers, and that the number ofthose workers available to assist with births varied substantially by municipality. One article attributed the high rate of referrals to tertiary levelhealth facilities to the inadequate skill of health care providers inlower-level facilities. Health care workers identified inadequate pay, transportdifficulties, lack of training or continuous learning opportunities, andinadequate supervision as important barriers to providing quality MNCH services.Pregnant women reported lack of confidence in the skill of providers as areason for not visiting health care facilities.33 butmore development is needed. Two major challenges for the country arecontinued improvement of the infrastructure and ensuring widespreadavailability of essential resources.Timor-Leste has progressed significantly in rebuilding its healthinfrastructure since it achieved independence from Indonesia, Stock-outs of commodities have been identified as a challenge toimplementing nutritionand vaccination programs, making it harder for providers to offer a quality service. Even whenskilled health workers are available equipment scarcity poses challenges,for example, when managing PPH patients during transportation via ambulance. Fuel shortages for ambulances result in a threat to successfulcritical care outcomes.Lack of adequate water and sanitation were identified as reasons why women donot seek antenatal care.One paper analyzed policy-level support for building maternity waiting homesand found that they were considered an appealing policy option because theyattract donor investment in infrastructure. There is little evidence to showthat waiting homes improve access to care for women in remote areas.One Government article outlined a 5-year plan for improving logistics,supplies and infrastructure to address quality within health care services.This review on the state of MNCH care in Timor-Leste found significant limitationsacross all 3 of the WHO quality standards including the provision and experience ofcare as well as cross-cutting standards.54 A fact that reinforces the need to continue support fordeveloping the knowledge and skills of health workers. In addition to clinicalguidelines and training, it is important to include regular refresher training,based on knowledge and skill gaps, and to support implementation with ongoingmentoring within an enabling environment.The review highlights the need for evidence-based guidelines and protocols formanaging critical health issues, particularly in maternal and child health, aspriority areas for intervention. Evidence-based practice of MNCH was positivelyinfluenced by workers’ skill-building through training and support forimplementation.31 Challenges associated with maternal and neonatal referrals havebeen widely reported in other low- and middle-income countries. Factors influencing referral systems in Timor-Leste are: low skill levels ofhealth care workers in charge of managing complications, lack of staff in healthfacilities, poor road networks, fuel scarcity and a lack of functioning vehicles,and poor weather conditions—particularly in the wet season. The challengesassociated with referral are exacerbated by the difficulties people face accessinghealth services, which include: lack of transport, poor road conditions, genderinequality, and poverty. These factors combine to severely limit access to appropriate levels of care,particularly for women and children in remote areas. In the face of thesechallenges, women and their families tend to rely on traditional medicine andassistance from traditional birth attendants.Access to health care and timely referral are ongoing challenges inTimor-Leste.In addition to improving referral between levels of service, research fromTimor-Leste recommends improving quality of care within health services, increasingthe availability and functioning of general patient transport services, and theprovision of travel subsidies to patients and their families.Studies related to experience of care appeared the highest number of times in theretrieved articles . Health providers, especially midwives whoprovide the majority of maternal, child, and reproductive health care, have acritical role in establishing a respectful and supportive relationship with theirclients, communicating information, and discussing care options with women and theirfamilies. Other research from Timor-Leste demonstrates the damage domestic violencedoes to women’s physical and mental health, examples of which include explosiveanger and long-term depression.4042 Health workers are often thefirst service providers women come into contact with as they seek care for injuriesor chronic health problems resulting from IPV. In these situations, it is criticalthat health providers can offer emotional support, safety planning and appropriatereferrals, in addition to medical care. However, in Timor-Leste it is common forhealth providers to blame women and to ask them what they did to cause theabuse.57 Although there are national guidelines for health providers toassist survivors of IPV, there is much to be done to improve communication, respect, and emotionalsupport to vulnerable people given the magnitude of violence against women,children, and people with disabilities in Timor-Leste.In Timor-Leste there are high rates of gender inequality and normalization ofviolence against women and children, which result in adverse health outcomes.56 Factors that contribute tothe lack of skilled health care workers in Timor-Leste include: limitedopportunities for continuous learning, insufficient supervision, poor workingconditions, lack of transport, and low salaries. A study of health worker migration in Asia Pacific reported that retention ofhealth workers in rural areas is a critical problem that could be addressed througheducation, personal and professional support, financial incentives, and regulatoryand health system supports.The availability of human and essential physical resources in the health sector arekey challenges identified in this review. A lack of skilled health care workers inrural settings has been a constraint to health service delivery since Timor-Leste’sindependence from Indonesia.This review also reinforced the need for sufficient physical resources, without whichskilled health workers may not be able to provide adequate care. In Timor-Leste, thedelivery of MNCH services continues to be hampered by a lack of infrastructure,stock-outs of essential equipment and medicines, poor water and sanitationfacilities, a lack of functional ambulances and emergency transport, and a lack oftime and privacy during consultations.60 However, these initiatives rely on accurate information andhealth system data. Poor quality data was a major challenge identified in thisreview33and has been documented in MNCH services in other low-resourcesettings.62 An important first step in the quality of care agenda inTimor-Leste is therefore improving case recording, and educating health providers asto its importance. In addition, building skills in data management and the use ofinformation for resource allocation, reflection, and for planning qualityimprovement initiatives. The country also requires strategies and practicalsolutions to overcome geographic constraints to accessing care. The challengesfacing health services are diverse, and therefore further work is needed to identifyspecific local needs, strengths, and resources and to consider how this knowledgecan be used to improve MNCH services in distinct parts of the country and at variouslevels of the system. Given the multi-layered and intersecting nature of qualitystandards, initiatives will need to be addressed in all parts of the health careservice, at national and municipal levels, in local health facilities, and byindividual health care workers. Stakeholder’s critical understanding of these vitalquality standards can enhance policies to improve MNCH services in Timor-Leste.Policy formulation on MNCH quality improvement in Timor-Leste requires criticallinkage of matching the existing situation with the available quality standards.This review has captured recent literature related to WHO quality standards in thedelivery of MNCH services in Timor-Leste. As the Ministry of Health and itsdevelopment partners focus on improving quality of care in Timor-Leste, the findingsprovide direction on specific areas that can be targeted for MNCH improvement. Whilemany of the issues identified are systemic and require high-level policy andsystem-wide support , other issues can be addressed at the provider and health facility level. There is agrowing body of evidence that quality improvement initiatives can be effective inlow-resource settings.