Spatially fractionated radiation therapy (SFRT), which delivers highly nonuniform dose distributions instead of conventionally practiced homogeneous tumor dose, has shown high rates of clinical response with minimal toxicities in large-volume primary or metastatic malignancies. However, prospective multi-institutional clinical trials in SFRT are lacking, and SFRT techniques and dose parameters remain variable. Agreement on dose prescription, technical administration, and clinical and translational design parameters for SFRT trials is essential to enable broad participation and successful accrual to rigorously test the SFRT approach. We aimed to develop a consensus for the design of multi-institutional clinical trials in SFRT, tailored to specific primary tumor sites, to help facilitate development and enhance the feasibility of such trials.Primary tumor sites with sufficient pilot experience in SFRT were identified, and fundamental trial design questions were determined. For each tumor site, a comprehensive consensus effort was established through disease-specific expert panels. Clinical trial design criteria included eligibility, SFRT technology and technique, dose and fractionation, target- and normal-tissue dose parameters, systemic therapies, clinical trial endpoints, and translational science considerations. Iterative appropriateness rank voting, expert panel consensus reviews and discussions, and public comment posting were used for consensus development.Clinical trial criteria were developed for head and neck cancer and soft-tissue sarcoma. Final consensus among the 22 trial design categories each  was high to moderate overall. Uniform patient cohorts of advanced bulky disease, standardization of SFRT technologies and dosimetry and physics parameters, and collection of translational correlates were considered essential to trial design. Final guideline recommendations and the degree of agreement are presented and discussed.This consensus provides design guidelines for the development of prospective multi-institutional clinical trials testing SFRT in advanced head and neck cancer and soft-tissue sarcoma through in-advance harmonization of the fundamental clinical trial design among SFRT experts, potential investigators, and the SFRT community. Pilot studies have shown low rates of toxicities and unexpectedly high tumor responses to SFRT in bulky metastatic and primary tumors.,,,,,Multiple single-institution studies have shown high response and local control rates in cohorts treated largely palliatively with GRID and Lattice SFRT.Thus, SFRT has the potential to broaden radiation therapy options for patients with locally advanced bulky primary, recurrent, and/or metastatic malignancies, for which with current techniques, the deliverable tumor dose is often severely compromised by normal-tissue tolerance limits.Based on these hypothesis-generating studies,,,,,,Design of such trials is challenged by SFRT's profound departure from familiar uniform-dose concepts and the requirement of complex biological modeling and nonintuitive dose-prescription metrics. Furthermore, SFRT platforms, techniques, dose and fractionation schemes have been variable. Currently, 2 profoundly different SFRT technologies are in use. GRID therapy,To address these obstacles toward development of multi-institutional prospective trials in SFRT, we sought to establish an in-advance common understanding and consensus among SFRT experts regarding the major design parameters and feasibility requirements for SFRT trial development, informed by the collective disease-specific clinical experience and by physics and biology expertise. The consensus effort comprised 2 major candidate primary disease sites—H&N cancer and soft-tissue sarcoma (STS)—and focused on the full range of clinical trial design criteria, including eligibility, stratification, endpoints, prescription dose and fractionation, target- and normal-tissue dose parameters, SFRT technology and technique, systemic therapies, patient assessments, and correlative science investigations.This consensus effort was conducted as part of the activities of the Radiosurgery Society (RSS) GRID, Lattice, Microbeam and FLASH Radiation Therapy Working Groups that were established, subsequent to an inaugural 2018 RSS–National Cancer Institute Workshop,A comprehensive literature search for GRID and Lattice SFRT was performed . The litThe overall process and rationale of the consensus procedure are described in detail in For each disease site, an anonymous 22-question voting survey with 1 to 11 subcriteria questions and the respective literature evidence tables (Appendices E1 and E2) were distributed to national and international experts with publications, scientific presentations, and/or clinical SFRT practice in the respective disease site (voting round 1). Voting for appropriateness and prioritization of each trial-design criterion was performed on a 1 to 9 scale  with addFor the analysis of voting results, in addition to descriptive statistics quantifying the appropriateness of each design criterion, a statistical model was developed  to quantA disease-specific consensus expert panel of 3 radiation oncologists, a physicist, and a biologist with scientific SFRT publications and/or presentations was established for each disease site to develop the consensus recommendations and guideline. The aggregated voting round 1 results were circulated among each disease-specific panel, reviewed, and discussed in sequential conference calls and communications, using modified Delphi techniqueThe drafts of the resulting consensus guidelines were posted on the RSS website for public comment. After review of the comments, the panel finalized the guideline as summarized in this article. The detailed guidelines are presented in Appendices E5 and E6.,,,The clinical trial design recommendations for H&N cancer were guided by 3 SFRT outcome studies of multiple disease sites containing H&N cancer patients,6,,,The consensus on eligibility and exclusion criteria is summarized in The panel unanimously recommended exclusion of tumors with both carotid invasion and skin involvement, or both carotid invasion and prior radiation therapy, based on fatal carotid bleeding after SFRT in a patient with carotid invasion and prior radiation,Patients with prior radiation therapy (moderate consensus), prior surgery, and/or (induction) chemotherapy (high consensus) are excluded, with the exception of prior surgery with no prior radiation to the target region. A separate clinical trial  is suggested for patients with postradiation recurrences.Stratifications according to T-stage and HPV status are recommended based on their strong influence on outcome. Stratification by SFRT technology—for example, GRID versus Lattice therapy (if Lattice is used in the future)—is recommended because of dosimetric differences .Local control and treatment related toxicity are recommended as primary endpoints. The feasibility of delivering SFRT according to the dosimetric and physics specifications,,,,Based on the outcome data6,Standardization of the GRID dose prescription, defined as the peak dose, is required. In addition, dosimetric and geometric characteristics of the heterogeneous dose distribution, such as dose volume histogram characteristics  and peak-to-peak distance, should be reported according to guidelines further described in the recent GRID physics and dosimetry white paper.,The SFRT target should consist of the involved nodal mass (GTV)6,Based on published data6,Based on current published data,6,Conventionally fractionated external beam radiation therapy (cERT) must be given after SFRT, because it has been demonstrated that tumor response is inferior when cERT is omitted.For the cERT component of treatment, conventional definitive dose regimens, specific to the H&N disease site, are prescribed. PTV doses are generally in the range of 70 to 72 Gy (2-2.12 Gy/fraction) to the gross tumor, 60 to 63 Gy to the high-risk subclinical target, and 50 to 56 Gy to the low-risk subclinical target (high consensus). Reduction of the definitive cERT dose below standard dose levels is not recommended because a reduced response rate of only 25% was reported with cERT doses of less than 75% of the planned definitive dose.Dose constraints to OARs for the cERT component follow those of standard practice without consideration of the dose contribution from the SFRT (high consensus). The SFRT contributions to OARs must be addressed during the planning of the SFRT component of treatment .Chemotherapy and targeted systemic therapy agents that are typically considered appropriate in conjunction with standard-fractionation radiation therapy for H&N cancer are acceptable for a clinical trial (high consensus). These agents typically include but may not be limited to platinum-based chemotherapies, taxanes, and cetuximab. Chemotherapy can be given concurrently with radiation therapy for the cERT component of treatment. However, systemic therapy should not be given during SFRT (high consensus). Typical schedules that have been used consist of delivering SFRT (without systemic therapy) on a Friday, followed by cERT and concurrent systemic therapy start within 72 hours on the following Monday.In the absence of published experience with combinations of SFRT and immunotherapy in H&N cancer, there was no consensus among voters on this combination. The panel favored not to include immunotherapy for an initial trial (moderate consensus) and to test combined therapy in a subsequent trial using guidance from the ablative stereotactic radiation therapy and immunotherapy experience, and future SFRT and immunotherapy experience.Patient evaluations before, during, and after treatment are recommended according to the standard of care for H&N cancer. These are detailed in The outcome endpoint of local/regional control in the neck is important but can be challenging to definitively characterize because of interinstitutional variability in response assessment and in the use and timing of postradiation neck dissection. Determination of local control should be based on the 3-month posttherapy positron emission tomography/computed tomography (PET/CT), using established response criteria; and on the need for postradiation neck dissection, including pathologic response at the time of neck dissection.To enable translational correlative science studies, specimen collection of blood and urine multiple times during radiation therapy should be strongly considered (high consensus). Although pretherapy tumor biopsies are available for correlative studies, tumor tissue sampling during the treatment course was considered not clinically practical or feasible based on the potential clinical risk. If possible and available, advanced functional and molecular imaging techniques such as vascular and metabolic imaging may provide noninvasive and non-tissue-altering approaches to characterize changes in functional tissue properties in response to SFRT during and after treatment.,,,As for H&N cancer, trial design recommendations for STS were based on multidisease series that included sarcoma patients and disease-specific series (Appendix E2). This experience comprised 2 studies of largely palliatively treated cohorts that contained sarcoma patients.,,,,Eligibility and exclusion criteria are summarized in Patients with stage IB-IIIB, grade 2 to 3, bulky ≥8 cm STS, who are planned to be treated with preoperative radiation therapy (high consensus), are eligible. Both neoadjuvant chemotherapy and no chemotherapy are permitted, reflecting the current practice pattern in STS. Prior resection, prior radiation therapy, and scleroderma  are exclusion criteria (high consensus).Tumor bulk, using the largest imaging-based tumor diameter of <12 cm versus ≥12 cm, and use of neoadjuvant chemotherapy versus no chemotherapy (see the section “Concurrent systemic therapy: Agents and timing”), should be stratified . Owing tThe feasibility of delivering SFRT according to the dosimetric and physics specificationsA dose range of 15 to 18 Gy in 1 fraction is an appropriate dosing regimen for clinical trials (high consensus), with the higher dose favored. The EUD of the SFRT regimen must be determined for sarcoma and for the normal tissues as described for H&N cancer.,,The SFRT target volume, based on clinical experience,Consideration should be given to excluding sensitive neural structures such as the brachial plexus from the SFRT volume and beam path (high consensus). Exclusion of OARs with a 1-cm margin, usually through secondary collimation with MLC blocking, are expected to achieve a negligible SFRT dose. It is also recognized that this may not be possible if these OARs are involved with a tumor. The skin surface dose from SFRT should be limited to <150% of the prescribed SFRT dose based on the STS brachytherapy experience.,,,,For an initial clinical trial, GRID therapy is the technology of choice, because all currently published clinical experience is in GRID therapy,,The cERT dose, following the SFRT fraction, is 50 to 50.4 Gy / 25 to 28 fractions to the PTV (high consensus) per RTOG trial regimens,Most commonly, the cERT course begins 1 to 2 days after SFRTConventional dose constraints to critical normal tissues are applied. The dose contribution from the SFRT is not counted toward the dose constraints (moderate consensus). For concerns regarding normal-tissue doses, the OAR dose should be reduced up front when planning the SFRT by adjusting field size and shape (see the section “SFRT: OAR constraints”).Neoadjuvant chemotherapy (prior to radiation therapy) and adjuvant chemotherapy after radiation therapy completion are acceptable. Agents considered acceptable in standard-of-care practice are allowable in clinical trials (high consensus).Concurrent chemotherapy, delivered during the radiation therapy course, is not considered permissible in an initial clinical trial (high consensus). Concurrent chemotherapy is inconsistently and not widely used in current practice, providing a rationale for its omission, along with the potential to introduce confounding variables for the interpretation of tumor control and toxicity outcomes.Immunotherapy was not considered to be recommended in an initial clinical trial (high consensus) but can be studied in subsequent trials or as a lead-in study as more combined STS radiation therapy and immunotherapy data emerge.Evaluations are presented in On-treatment evaluations should consist of a standard weekly response, toxicity, QOL assessments, and patient-reported outcomes. Specimen collection of blood and urine multiple times during radiation therapy for translational correlative studies are feasible and strongly recommended (high consensus). Tumor biopsies during the treatment course are considered not clinically feasible (high consensus). Uniquely in the preoperative radiation therapy setting, the surgical specimen after radiation therapy provides an important potential resource for the prospective study of post-SFRT molecular markers in both tumor and normal tissue.After radiation therapy, preoperative response assessment is recommended, preferably with magnetic resonance imaging, using the Response Evaluation Criteria in Solid Tumors, quantitative imaging assessment of tumor necrosis (>90% necrosis), and standard clinical examination (high consensus) at 4 to 8 weeks after radiation therapy. Evaluations should be performed in conjunction with QOL assessments and patient-reported outcomes (high consensus).Pathologic tumor response, as routinely assessed in standard of care, provides an important outcome assessment for SFRT response in STS clinical trials. Assessment of negative-margin resectability, R0 versus R1 resection, and pathologic criteria of tumor response including quantitative histologic assessment of necrosis of >90%History and clinical examination are indispensable for the assessment of function and toxicity outcomes. Clinical examination and imaging surveillance schedules should follow the standard of care  and be cThe pilot experience that has defined SFRT dose and techniques and shown promising tumor control, toxicity outcomes, and early survival outcomes, has reached an inflection point that enables the development of multi-institutional SFRT trials in definitively treated bulky primary tumors.SFRT for both STS and H&N cancer share common properties of high ablative stereotactic radiation therapy dosing, generally excluding OARs; and are administered in close time proximity before conventional radiation therapy or radiation therapy and chemotherapy.Standardization of the novel, nonconventional physics and dosimetric parameters with inherent dose and response modeling of the heterogeneous dose to tumor and normal structures is essential for the feasibility of SFRT trials and for their success in generating meaningful results. The inclusion of well-conducted translational science into clinical trial design is critically important to investigate in clinical patients the preclinically observed biological mechanisms and potential immunologic phenomena of SFRT.This development of guidelines for clinical trial design is a novel concept to establish broad consensus (through ample a priori communication and vetting) among the respective scientific and clinical communities, well ahead of clinical trial design and development. We have adapted existing consensus process models that have been in use for clinical care guidelines, which are generally based on ample published data and large numbers of experts. We applied and further developed these concepts for the requirements of consensus development in the different domain of clinical trial design, which has to build on much sparser, less mature pilot data and fewer experts, but nonetheless requires agreement among the broader community to facilitate trial success. Intense engagement and consensus building among clinical, physics, and biology expertise enabled identification of current knowledge gaps and development of design strategies to address them in clinically feasible trials.The trial design recommendations presented herein are based on the current status of knowledge in SFRT and the developed common understanding among SFRT experts and community. Although they may provide guidance for clinical trial design and embedded translational studies, new data, longer-term outcome results, and larger patient cohorts may further refine, adapt, or modify these initial concepts. Ultimately, these consensus recommendations should be individualized by the respective investigators and their teams pursuing clinical trials in SFRT.


Youth is a critical period in the development of maladaptive eating behaviors. Previous systematic reviews suggest the etiological significance of parent-child relationships for the onset of disordered eating in youth, but less is known about the role of parenting styles. This rapid scoping review aimed to identify whether research supports the role of parenting styles in the development of disordered eating symptoms among youths. Sixteen studies, retrieved from three databases , met the inclusion criteria: original studies, published in English, examined the effect of parenting styles (authoritative or neglectful) on cognitive (drives for thinness and body dissatisfaction) and behavioral (weight control behaviors) disordered eating outcomes, among young people up to 18 years of age. Studies supported an association between various youth disordered eating symptoms such as unhealthy weight control behaviors, and experiences of adverse parenting styles characterized by high levels of control and low levels of responsiveness. Associations between adverse parenting styles and youth disordered eating were frequently indirect and differed depending on the sex of the parent and offspring. Synthesis of findings was limited due to variation in the operationalization and measurement of parenting styles, family context and disordered eating across studies. Longitudinal and standardized research is required to better understand the dynamic associations between parenting styles and youth disordered eating. Implications for family-based care in clinical practice are discussed. Disordered eating (DE) refers to maladaptive attitudes, behaviors, and cognitions related to eating and weight , and hasThe influence of the parent-child relationship on offspring DE has been explored . One comParenting styles may be viewed as a process through which attachment with caregivers is established and maintained across development . ParentsWithin such risk pathways, youths’ experience of adverse parenting styles may be conceptualized as a non-abuse adverse life experience (ALE). Non-abuse ALEs refer to adverse experiences excluding abuse  , and areAlthough some studies have examined the impact of adverse parenting styles on DE symptoms in youth, the results lack consistency. Though demanding  and unacPrevious systematic reviews have evaluated the etiological significance of the parent-child relationship for the onset for both clinical and subclinical maladaptive eating behaviors in youth. Insecure attachment styles  and dysfIn this rapid scoping review, a systematic search of the literature was conducted . SD & CHParenting style and teenage or childhood (with synonyms) were used as search terms, combined with the following : disordered eating and maladaptive eating. Full search strings are included in the PsycArticles, PsycInfo, and CINAHL were searched in March 2021 to gather primary published studies. The BASE database was also searched for gray literature for additional relevant sources. Included studies met the following requirements: (1) included a youth sample ; studies solely measuring parenting behaviors relating to food or exercise, such as food restriction e.g., , were exOne hundred and fifty eight studies were identified from initial database searches. Following the removal of duplicates and screening, 122 studies were excluded, primarily for not including a measure of parenting style or for using an adult sample. Full-texts of the remaining 34 studies were evaluated, yielding 16 eligible studies for inclusion. Studies were excluded for using participants with an ED diagnosis or not assessing offspring DE.Data from selected studies were extracted by CH and included studies’ author; year; country; design; sample characteristics; measure of parenting style and DE; parents assessed; risk of bias; and findings . Given tA modified version of the Effective Public Health Practice Project (EPHPP) Quality Assessment Tool for Quantitative Studies  was usedEight studies were cross-sectional and eight were longitudinal . All stuvia offspring self-report and utilized a range of tools. Parental control scales were implemented in three studies, including the Psychological Control Scale Youth Report (Parenting styles were assessed h Report , 2009. Th Report .DE outcomes were measured using self-report tools with the exception of one study, where parents reported on offspring DE using the Kiddie Schedule for Affective Disorders and Schizophrenia . Of the Included studies used a range of statistical analysis techniques, though this information was missing in one study . RegressOverall, the divergence in the methodologies, measures and reporting in included studies limited the summarization and synthesis of findings within this scoping review.Both paternal  and mateand high control predicted increased odds of, and more severe, DE. Two studies also aggregated findings at multiple time points throughout the study (Similar to the cross-sectional results, adverse parenting presenting varying levels of responsiveness and demandingness was associated with a substantial range of operationalizations of DE. High levels of parental control predicted unhealthy WCBs  and bodyhe study . Associahe study  and diffhe study . Finallyhe study .The present review focused on associations between parenting styles and DE presentation in youth. Most studies provided preliminary support for an association between symptoms of DE and experience of various adverse parenting styles e.g., , althougA number of characteristics of adverse parenting styles were associated with youth DE. Parenting styles that were perceived as controlling were associated with a range of youth DE outcomes . SpecifiHowever, many studies found indirect effects of adverse parenting styles on DE; only one study established a direct association between high paternal demandingness, low responsiveness and DE . AssociaFurthermore, longitudinal studies found interactions between parenting styles and DE varied throughout youth . The teeAlthough many studies assessed and aggregated maternal and paternal parenting styles, some studies converged parental contributions into a unitary construct of parenting in measurement  and analA significant differentiator of study quality was researchers’ consideration of the confounding effects of co-variates of parenting style. Higher quality studies situated parenting styles in the broader family context, for example collecting self-reported parental marital status  and numbOnly one study implemented a multi-modal procedure to assess parenting style , therebyAdditionally, directional influences of parenting styles cannot be inferred from reported DE symptoms in cross-sectional studies. Though Finally, selection bias may be present as review results were limited to the English language. However, as the majority studies were conducted by English speaking countries, the risk of excluding additional relevant findings is anticipated to be low.Findings from the present review have implications for clinical practice. The prevalence of reported DE symptoms in youth across studies demonstrates the clinical necessity of intervention into maladaptive parenting styles. Clinicians must implement a patient-centered recovery model e.g.,  and consThis rapid scoping review evaluated 16 studies to assess whether parenting style could be a risk factor for youth DE. Exposure to demanding, unresponsive, or a combination of these, parenting styles both predicted and correlated with reports of various symptoms of DE. However, included results were often conflicted, and comparative conclusions concerning the influence of adverse parenting styles on youth DE are limited due to the heterogenous operationalization and measurement of parenting styles, family context, and DE outcomes. Therefore, the present review does not establish a definitive account of the etiological influence of parental style to the onset of DE in youth. Further research implementing longitudinal and standardized procedures is essential for good quality research into parenting styles.CH: conceptualization, methodology, investigation, and writing – original draft. BM: writing – review and editing. SD: conceptualization and writing – review and editing. All authors contributed to the article and approved the submitted version.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.


Infants suffering from neonatal chronic lung disease, i.e., bronchopulmonary dysplasia, are facing long-term consequences determined by individual genetic background, presence of infections, and postnatal treatment strategies such as mechanical ventilation and oxygen toxicity. The adverse effects provoked by these measures include inflammatory processes, oxidative stress, altered growth factor signaling, and remodeling of the extracellular matrix. Both, acute and long-term consequences are determined by the capacity of the immature lung to respond to the challenges outlined above. The subsequent impairment of lung growth translates into an altered trajectory of lung function later in life. Here, knowledge about second and third hit events provoked through environmental insults are of specific importance when advocating lifestyle recommendations to this patient population. A profound exchange between the different health care professionals involved is urgently needed and needs to consider disease origin while future monitoring and treatment strategies are developed. As the most common chronic lung disease in infants, Bronchopulmonary Dysplasia (BPD) is associated with long-term sequelae that persist into adulthood , 2. DespThe disease is classified into three different severity grades  according to the need for supplemental oxygen and/or ventilator support for >28 days of life, or beyond 36 weeks postmenstrual age (PMA) . The chaLarge clinical trials have identified numerous risk factors for the development of BPD, including congenital and nosocomial infections, mechanical ventilation, and oxygen toxicity –17. PoorWith regard to the genetic background impacting on the clinical course, prior work demonstrates that gene polymorphisms account for 53% of the variance in BPD . IdentifEscherichia coli) that are likewise associated with BPD development  enhances lung vascular and airway smooth muscle contraction and reduces nitric-oxide relaxation in the neonatal rat lung, the opposite occurs in adults . In lineThe outlined injury effects ultimately result in the impairment of lung growth based on significantly imbalanced growth factor signaling. Orchestrating the interaction of the epithelial, mesenchymal, and endothelial cell compartment during the fine-tuned development of the gas exchange area, Notch and Wingless Int-1 (Wnt), the fibroblast and platelet derived growth factor  as well as the BMP and the vascular endothelial growth factor (VEGF) play a critical role –89.The release of cytokines such as the transforming growth factor (TGF) –β, tumor necrosis factor (TNF) alpha and interleukins, e.g., IL-1beta in response to lung inflammation and subsequent events such as ECM remodeling and cellular injury significantly contributes to the imbalance in growth factor signaling and leads to the activation of different transcription factors enhancing apoptosis in numerous cell types –92. The Both direct effects of shear stress, oxygen toxicity, inflammation, and hormonal regulation as well as subsequent impairment of growth factor signaling alters critical events in endoderm to mesoderm transition and myofibroblast proliferation and leads to severe alterations of the pulmonary scaffold , 106. InThe significant changes to the structural integrity of the ECM not only affect its function as a scaffold for the formation of alveoli and capillaries but as well-reveal a significant memory function through defining the fate of cells populating the developing organ , 116. ThWith increasing survival of infants with BPD, attempts to minimize long-term pulmonary impairment (and associated neurologic complications) has become the main focus of perinatal care , 120. NoAfter birth, early pulmonary dysfunction is characterized by diminished lung compliance, tachypnea, and increased minute ventilation resulting in increased work of breathing with or without subsequent oxygen dependency. This clinical picture can be accompanied by an increase in lung microvascular filtration pressure that may lead to interstitial pulmonary edema as shown in animal experiments . The inc2 at discharge  and gas transfer for those born extremely premature at school age when compared to age matched controls, not considering BPD status. Mean difference in FEV1 sum up to a total of 600 ml when comparing infants with extreme prematurity at birth and the respective healthy controls. Significantly lower peak workload and higher respiratory rates in combination with lower tidal volumes during peak exercise and increased residual capacity in these infants may reflect the effect of hyperinflation due to airway obstruction and/or altered pulmonary chemoreceptor function, and suggest the presence of persistent airflow limitations and reductions in alveolar surface area.In the later course of disease, BPD is a significant risk factor for persistent wheeze and the need for inhalation therapy  affecting about 20–30% of infants with BPD at 6 and 12 months of age , 135. ReIn most severe cases symptoms either persist into adulthood  or show Taken together, the functional data available suggest that early lung injury in preterm infants leads to abnormalities in lung function (and immunity) in infancy and early childhood with significant pulmonary problems persisting in the most severely affected infants. The predisposition for lung function decline in adult survivors of preterm birth is suggested by data obtained in early and later adulthood with lung function measurements in infancy being an important predictor for later lung disease and the risk for (early) lung function decline. If performed during infancy and childhood, pulmonary function tests have the potential to identify individuals at risk of long-term respiratory sequelae and will help to elucidate the impact of secondary injuries, e.g., first and second hand smoke as well as viral infections on this trajectory . ImportaTo conclude, the unique response of the developing lung to early postnatal injury is characterized by sustained inflammatory processes, ECM remodeling and a pronounced alteration in growth factor signaling that ultimately results in the characteristic histopathologic picture of impaired alveolar and vascular development. These processes are critically determined by the pulmonary capacity to respond to and compensate for environmental challenges inducing oxidative stress and imbalance in growth factor signaling . We now All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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.


On 4th October 2021, the Nobel Prize in Physiology or Medicine 2021 was awarded jointly to David Julius and Ardem Patapoutian "for their discoveries of receptors for temperature and touch."The senses of temperature and touch are among the most basic physiological functions in animals and humans. Stimuli from the surrounding environment or physical objects interact with receptors, mainly temperature and tactile sensory receptors, and are converted into information, or neural signals. Subsequently, all the encoded neural signals are transmitted through afferent (or sensory) neural fibers to interneurons or the central nervous system, and thence through efferent neurons (or motor neurons) to effector organs, for example muscles. These steps form a complete reflex arc comprising the body's response to external stimuli. Perceptions of the external stimuli help our bodies to react, to make decisions and motor responses, so that we can feel, interpret and interact with our external and internal environment.In mechanistic research, laboratory animal experiments focus on several major questions: What are the molecular bases to sensing heat, cold or mechanical force? How do external stimuli convert into electrical nerve signals? The winners of this year's Medical Prize investigated and identified the receptors for temperature and touch sensation. Their research used different species of laboratory animals and different strains of rodent animal models to unravel these questions.2For centuries, people have sought the secret of temperature perception. Since ancient times in China, the theory of cold/hot properties has been the most basic aspect of Traditional Chinese Medicine (TCM).Treatise of Man (or L'homme in French). Centuries later, the 1944 Nobel Prize in Physiology or Medicine was awarded jointly to Joseph Erlanger and Herbert Spencer Gasser "for their discoveries relating to the highly differentiated functions of single nerve fibres."In western countries, exploration of temperature sensation dates back to the 17th century, when the famous French philosopher René Descartes postulated that heat could send signals to the brain, in his book N‐vanillyl‐6‐nonenamide), can induce a ‘hot’ and burning sensation in people. In the late 1990s, Dr Julius and colleagues tried to isolate a functional cDNA encoding a capsaicin receptor in sensory neurons. In 1997, they shared their discovery of a non‐selective cation channel TRPV1 , which can also be activated by noxious temperature stimuli. Using laboratory rats for their experiments, they found that VR1 is expressed in adult rats in primary sensory neurons, in a subset of sensory ganglion cells, including dorsal root ganglia (DRG) and trigeminal ganglia (TG) mainly in smaller‐diameter cell bodies instead of large‐diameter ones.−/− mice showed little thermal hyperalgesia behavior, while the mechanical pain remained. This indicated that the TRPV1 receptor is essential to thermal hyperalgesia sensation.The story of finding the molecular bases for sensing heat or cold began with chili peppers. When eating (or even touching) spicy chili peppers, the active component, capsaisin , and the first awards of Physics, Chemistry, Peace and Literature Prizes were made in 1901. Since then, there have been 112 Nobel Prizes in Physiology or Medicine and 224 Nobel Prize laureates, most of whom relied on animal models in their experimental medical research. With further developments in science technology and increasingly open platforms for science sharing, experimental medicine based on laboratory animal resources will generate even more impetus for better research, better science and a better world.The authors have declared no conflicts of interest.Yu Zhang designed the project and wrote the manuscript; Dongyuan Zhang collected the references and wrote the manuscript; Chuan Qin designed the project and approved the final version.


SOMMA is an NIA-funded cohort study to identify biological determinants of mobility and fitness. The overall aim of SOMMA is to use biopsies, novel biomarkers, advanced imaging, and intensive physical and cognitive assessments to elucidate the biological processes that contribute to changes in mobility and physical fitness with aging. SOMMA will recruit 875 people age 70+ (of whom about 200 have been enrolled.) We take biopsies of the vastus lateralis muscle to quantify mitochondrial content and function of the electron transport chain. We use 31PMR spectroscopy to quantify mitochondrial capacity to generate ATP in quadriceps muscle (ATPmax). We will quantify other biological properties in biopsies including denervation, autophagy and accumulated biochemical damage and use gene expression to discover pathways that contribute to mobility and fitness. SOMMA uses MR for quadriceps volume and D3Cr dilution for total skeletal muscle mass, cardiopulmonary exercise testing to measure fitness (VO2 peak). We are also making many other intensive assessments of physical and cognitive function. Mobility endpoints include baseline and three year change in 400 m and 4 meter gait speed and fitness. SOMMA is building a large biobank of muscle, adipose blood, and urine specimens that will be available for ancillary studies. In this Symposium, we will present results from analyses of associations between muscle mitochondrial function and strength, muscle mass, cognitive performance, gait speed, and fitness. The symposium will also preview opportunities for collaborations and ancillary studies with SOMMA.


We examined the mental health and quality of life (QoL) outcomes and their correlates of school-aged survivors of neonatal jaundice (NNJ), hypoxic-ischemic encephalopathy (HIE), and a comparison group. The Child Behavior Checklist and the Pediatric Quality of Life Inventory were administered to assess the mental health and QoL of 375 children  aged 6 to 12 years [Median age 9 (interquartile range 7 to 11)]. The results showed that survivors of NNJ and HIE have mental health problems and QoL similar to the comparison group. Maternal mental health was the predominant covariate of mental health and QoL in survivors of NNJ and HIE. This result could indicate that mothers with mental health problems are more likely to have children with mental health issues, but also that caring for children with these adversities may affect mental health well-being of the caregivers. There is a need for early mental health screening and psychosocial intervention for caregivers and their children to enhance both their mental health and QoL. Neonatal jaundice (NNJ) and hypoxic-ischemic encephalopathy (HIE) are common problems globally, but are most prevalent in low- and middle-income countries (LMICs) such as those in sub- Saharan Africa (SSA) , 2. NNJ In high-income countries (HICs), most children survive NNJ and HIE without significant morbidity due to availability of preventive strategies, early diagnosis, and advanced care and treatment. In contrast, in LMICs, especially in rural areas such as Kilifi, about 50% of mothers deliver their babies at home by unskilled birth attendants . TherefoMoreover, survivors of these conditions are likely to be impaired in different developmental domains due to lack of proper guidelines for care and treatment , lack ofChildhood infections are likely to interfere with the development of specific brain regions such as the prefrontal cortex and the subcortical ganglia regions that regulate behaviour and emotions and may develop mental health problems  such as Although some degree of EBPs are expected in young children, persistent problems  may indiThe long-term outcomes of NNJ and HIE are best understood using dynamic models of human development, such as the bioecological model of human development. According to this model, child development is influenced by both biological and environmental factors to which the child is exposed . A childWhile the literature presents some data on the mental health outcomes of survivors of NNJ and HIE, most of these studies are based on data from HICs , 29, 30.We conducted a cross-sectional study of children aged six to twelve years with a past admission history of NNJ or HIE at Kilifi County Hospital (KCH).All study procedures and assessments were conducted at the Centre for Geographical Medicine Research-Coast (CGMRC) Neuro-assessment unit situated at the Kenyan Coast. We utilised the Kilifi Health Demographic Surveillance system (KHDSS)  to recruChildren who took part in this study were admitted to KCH in their neonatal period with a diagnosis of either NNJ or HIE. The diagnosis of NNJ was based on clinical laboratory measurement of total serum bilirubin (TSB) as well as medical history and examination during the first 28 days of life. NNJ was defined as a TSB level of > 85 µ/mols/l recorded in the clinical notes. HIE diagnosis was based on the clinical diagnosis recorded by a clinician. HIE diagnosis was given if a child; had convulsions, was unable to breastfeed, had apnoea, and or poor motor tone . The comp = 0.05) to detect medium effect sizes between the affected groups and the comparison group. The number of participants in the comparison group was calculated using frequency matching, where 20 participants were required in each age band (6–12 years).G-power 3.1 software calculations gave an estimation of 127 participants in the NNJ group  and 90 pThe CBCL/6-18  was usedThe PedsQL  is a 23-The PedsQL has four main scales: physical functioning, emotional functioning, social functioning, and school functioning. Each negatively keyed item is measured with a five-point Likert scale that ranges from “1 = never” to “5 = almost always”. After reverse scoring of the item scores, the scale scores are computed as the sum of the item scores in each scale. These scores are transformed to a 0–100 scale such that higher scores indicate better HRQL.In this study, a Physical Health Summary Score was computed by summing the reversed individual item scores of the physical functioning scale, and a Psychosocial Health Summary score by computing sum of the items over the number of items answered in the emotional, social, and school functioning scales. A Total Scale Score was computed as the sum of all the items over the number of items answered on all the four scales . The PedA trained clinician conducted a physical examination to determine the motor and sensory neuron responses of the children using a detailed neurological proforma adapted for this study, from a proforma that has been extensively used within the study setting .We did anthropometric assessments and measured the children’s weight, height, middle-upper-arm measurements in centimetres as per the recommendations of the World Health Organization (WHO) . The calA clinician conducted structured interviews with the caregivers to document the biomedical risk factors. Potential biomedical risk factors included in this study were abnormal pregnancy , place of birth , abnormal delivery , delayed crying at birth, breathing problems at birth, hospital admission, presence of febrile seizures, and presence of any other medical problem after discharge from hospital.Caregivers’ demographic variables that were assessed include sex, age, level of education, marital status, and religion. We also captured information about the child’s sex, age, and number of years of schooling.The Patient Health Questionnaire (PHQ-9) ; Externalizing ; and Total problems  (Table p = 0.515). The survivors of NNJ and HIE had higher but not significantly different scores on Psychosocial Health ; Physical Health ; and Total Scale  compared to the comparison group . Maternal mental health, neurological, and medical problems predicted Externalizing problems . Maternal mental health  was the only factor with an independent contribution. Family environment, maternal mental health, and delivery problems predicted Total problems . Maternal mental health  remained the only factor contributing independently. Table The multiple regression analysis with maternal lack of education, family environment, maternal mental health, and medical problems predicted the Internalizing problems scale , with maternal mental health  and hospital admission  as independent predictive factors. Stunted growth, maternal lack of education, family environment, maternal mental health, abnormal delivery, crying problems, feeding problems, and neurological problems predicted PedsQL Physical Health Summary Score . Family environment ; maternal mental health ; abnormal delivery , and breast-feeding problems  were the independently contributing factors. Stunted growth, family asset, maternal lack of education, family environment, maternal mental health, crying problems, hospital admission, and neurological problems predicted Total Scale Score . Maternal mental health remained the only factor independently associated with Total Scale Score   = 7.20, R7 = 7.20,R2 = 0.11, p = 0.015], with presence of fits as the only independent factor . Stunted growth, family environment, maternal mental health, crying problems, and presence of fits predicted Externalizing problems . Maternal mental health  and presence of fits  appeared the only independent predictive factors. Stunted growth, family environment, maternal mental health, crying problems, and presence of fits predicted Total problems . Maternal mental health  and presence of fits  remained as independent predictive factors. Table The multiple regression analysis with family environment, maternal mental health, and presence of fits predicted Internalizing problems , with maternal mental health  as the only independent factor. Stunted growth, family asset, hospital admission, medical and neurological problems did not predict PedsQL Physical Health Summary Score . Stunted growth, family asset, maternal lack of education, maternal mental health, hospital admission, medical and neurological problems predicted Total Scale Score , with maternal mental health  as the only independent predictive factor  = 3.92, We investigated mental health outcomes and QoL of school-aged survivors of NNJ and HIE and a community comparison group and the correlates associated with the mental health and QoL outcomes of survivors of NNJ and HIE. The findings indicate that the survivors of NNJ and HIE have comparable EBPs and QoL functioning as the community comparison group. Poor maternal mental health was associated with elevated EBPs in all the three broadband CBCL scales as well as with lowered quality of life in both survivor groups.The findings of this study indicate that survivors of NNJ or HIE have mental health outcomes comparable to children without neonatal insults. Our results are consistent with the study by Vanborg et al. (2014), who reported that survivors of NNJ were not at an elevated risk of experiencing mental health problems compared to unaffected peers . SimilarVarious factors may explain our observations. First, earlier studies indicate that Kenyan children in the general population have elevated EBPs  compared to other multicultural standards . TherefoWe found no significant differences in the QoL of survivors of NNJ and HIE when compared to healthy children. To the best of our knowledge, there are no studies that have investigated the QoL of school-aged survivors of NNJ and HIE, thus making it difficult for us to interpret the results in the context of earlier findings. However, investigations into the QoL of survivors of NNJ and HIE are vital as health is regarded as the state of complete physical, mental, and social well-being and not merely the absence of disease . TherefoAlthough there are limited studies on the associations between maternal mental health and outcomes in survivors of NNJ or HIE, our finding that poor maternal mental health is associated with elevated levels of EBPs and lowered QoL in school-aged survivors of NNJ or HIE is consistent with other population-based studies , 50–56. Our finding that having seizures during admission was associated with elevated EBPs among survivors of HIE is similar to results in studies which have reported that EBPs are common in children with acute symptomatic seizures .The findings of this study should be cautiously interpreted, given the following limitations. First, the definition of NNJ included children with mild and moderate NNJ and few children had severe NNJ. Second, the mothers of the participants may have suffered recall bias, especially about the medical history of their children at the neonatal stage. Third, we could not perform subgroup analysis based on the severity of HIE as there was limited data on the Apgar score of the children with HIE. Fourth, as we used parental reports to explore the EBPs and QoL in their children, the responses of the parents could include a subjective component and be biased by the mental health state of the caregivers.Additionally, parents may lack insights into their children’s mental health state. Teachers’ reports could have added more insights into the children’s mental health functioning as the classroom setting may give the teachers a better opportunity to detect mental health problems . AlthougNeonatal jaundice and HIE are common clinical problems that affect babies during the first days of life and are associated with child mortality and morbidity. Despite the high prevalence of NNJ and HIE in SSA, there is no data on long-term mental health and quality of life outcomes of survivors of NNJ or HIE in SSA. The current study examined the mental health and quality of life outcomes of school-aged survivors of NNJ, HIE, and a comparison group and the correlates of these outcomes in Kilifi, Kenya. We followed 375 participants  aged 6–12 years. We used the CBCL and PedsQL to assess the mental health and quality of life, respectively. Our results suggest that both the survivors of neonatal insults and the unaffected peers have comparably elevated mental health problems and quality of life outcomes. The association of poor maternal mental health to elevated EBPs and lowered QoL suggests a need for early psychosocial and clinical intervention for caregivers and their children to reduce the children’s risk for later development of EBPs and improve functioning in Kenyan children.


Mental health disorders are a leading cause of medical disabilities across an individual’s lifespan. This burden is particularly substantial in children and adolescents because of challenges in diagnosis and the lack of precision medicine approaches. However, the widespread adoption of wearable devices  that are conducive for artificial intelligence applications to remotely diagnose and manage psychiatric disorders in children and adolescents is promising.This study aims to conduct a scoping review to study, characterize, and identify areas of innovations with wearable devices that can augment current in-person physician assessments to individualize diagnosis and management of psychiatric disorders in child and adolescent psychiatry.This scoping review used information from the PRISMA  guidelines. A comprehensive search of several databases from 2011 to June 25, 2021, limited to the English language and excluding animal studies, was conducted. The databases included Ovid MEDLINE and Epub ahead of print, in-process and other nonindexed citations, and daily; Ovid Embase; Ovid Cochrane Central Register of Controlled Trials; Ovid Cochrane Database of Systematic Reviews; Web of Science; and Scopus.The initial search yielded 344 articles, from which 19 (5.5%) articles were left on the final source list for this scoping review. Articles were divided into three main groups as follows: studies with the main focus on autism spectrum disorder, attention-deficit/hyperactivity disorder, and internalizing disorders such as anxiety disorders. Most of the studies used either cardio-fitness chest straps with electrocardiogram sensors or wrist-worn biosensors, such as watches by Fitbit. Both allowed passive data collection of the physiological signals.Our scoping review found a large heterogeneity of methods and findings in artificial intelligence studies in child psychiatry. Overall, the largest gap identified in this scoping review is the lack of randomized controlled trials, as most studies available were pilot studies and feasibility trials. The global burden of mental illnesses is daunting. In 2013, mental illnesses, such as major depression (2nd), anxiety disorders (7th), schizophrenia (11th), dysthymia (16th), and bipolar disorder (17th), were listed as some of the leading causes of years lived with disability . With thlearn the abilities by processing massive data sets through multilayered mathematical models  and training methodologies  improves the AI model’s predictive confidence  as  as 19] aWe identified what was the extent of literature on the use of wearable devices in the form of AI in child and adolescent psychiatry. We aimed to gain insight into the following research objectives: (1) understand how wearable devices are being used in child psychiatry by exploring the types of devices that are being used, investigating how these devices are being used in child psychiatry , and researching which physiological signals are being measured by these devices and (2) identify how the clinical knowledge of various pediatric psychiatric disorders has been expanded through the use of AI, specifically wearable devices.A comprehensive search of several databases was performed on June 25, 2021. The search was restricted from the year 2011 through the date the search was conducted. The results were limited to English language articles. Animal studies were excluded from this study. The databases searched were Ovid MEDLINE (≥1946) and Epub ahead of print, in-process and other nonindexed citations and daily ; Ovid Embase (≥1988); Ovid Cochrane Central Register of Controlled Trials (≥1991); Ovid Cochrane Database of Systematic Reviews (≥2005); Web of Science Core Collection via Clarivate Analytics (≥1975); and Scopus via Elsevier (≥1788).The search strategy was designed and conducted by an experienced librarian (LH), with input from the study investigators (APA and MR). Controlled vocabulary supplemented with keywords was used to search for studies. The actual strategy, listing all the search terms used and how they were combined, is available in The study selection process was divided into two phases: (1) title and abstract screening and (2) full-text article screening. For the first phase, 2 reviewers (VW and JW) screened the articles and either excluded them or included them on the source list. The resulting source list was reviewed by 2 other reviewers (APA and MR). A full-text article review was then performed by 2 reviewers (VW and JW) and the final source list was created.Most of the study data were extracted by a single researcher (VW). Another researcher (JW) helped complete 1 column and reviewed the table after it was completed. The following information was included in the table: year, sample population (size and demographics), psychiatric diagnosis, age range, wearable device used, and the measured physiological symptoms. The studies were divided based on the participants’ main diagnosis: autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and internalizing disorders (IDs).This proposed scoping review did not require ethics or institutional review board approval, as data were collected through the review of published peer-reviewed literature and gray literature. The results will be submitted for publication in an open-access peer-reviewed journal and presented at relevant medical and engineering conferences.The initial search yielded 344 articles. In all, 2 researchers (VW and TJW) completed the title and abstract screening process to narrow down this list. They reviewed papers independently, and disagreements were reviewed by 2 additional researchers (APA and MR). During this step, 89.2% (307/344) articles were omitted because they did not satisfy the inclusion criteria. The criteria for inclusion of studies for review in the first round of screening were as follows: the study must use a wearable device that passively tracked physiological variables in real time (objective measurements) and the device must be worn by a patient who had been diagnosed with one or more of the following psychiatric disorders: oppositional defiant disorder, conduct disorder, mood disorder , ADHD, learning disability , autism, or psychotic disorder. A full-text screening of the remaining 10.8% (37/344) articles was conducted by the same 2 researchers (VW and TJW). Given our focus on child and adolescent psychiatric illnesses, the criteria for study inclusion were accordingly altered to focus on child and adolescent psychiatric patients only (aged 0-18 years), wherein studies were written in English and published before January 1, 2021. Eligible designs included randomized controlled trials, nonrandomized experimental studies, cohort studies, and case-control studies. In addition, studies that focused on motor impairment were excluded. The PRISMA flow diagram for the study selection process is illustrated in The studies on the final source list were published between 2011 and 2021, and were spread across the world with most being conducted in the United States. In addition, the growth rate of research in this field increased substantially after 2018. The following sections provide a synopsis of each of the sources organized into the 3 categories previously outlined.Most studies  ,33,36,38A longitudinal study by Di Palma et al  mediatedSeveral studies used electroencephalography (EEG) in addition to ECG measures ,25. BileMany of the studies used wrist-worn biosensors ,27,36. SWilson et al  used weaA study by Krupa et al  also useAn intervention study by Pfeiffer et al  evaluateA small percentage of the studies  ,30,34,35In all, 11% (2/19) of studies used a smart watch application ,30. LeikMunoz-Organero et al  used 4 tThe final study in this category aimed to develop an objective method of evaluating the therapeutic effects of ADHD treatments by placing an accelerometer in their smart watch that recorded the movements of these patients . The varA study by Faeda et al  used an A few studies  ,32,37 inburned out quicker during the bubbles task and that it helped identify depressive, anxious, and trauma-related disorders. On the other hand, the snake task helped identify children with withdrawn, anxious, and depressive problems, oppositional problems, and specific phobias. Similarly, the speech task identified children with withdrawn, anxious, and depressive problems. After analyzing these results, they found that the phenotype from features that measured reward responsiveness could accurately detect children with underlying internalizing psychopathology with 75% accuracy.McGinnis et al  aimed toRedd et al  investigThe primary outcome of this scoping review was a characterization of 19 studies of child and adolescent patients with ASD, ADHD and ID that gathered data through practical means and used passively gathered data for various prediction mechanisms.From the included studies we were able to provide a descriptive analysis of currently available devices used to passively gather data in AI trials. Most of the studies used either ECG strap or wrist-worn biosensor. This is somewhat surprising as, for example. studies by Fioriello et al  and KushThe information obtained from this review can guide future trial development. Only 1 trial  had a hiperforming breathing exercises for 30 seconds) may be helpful in forcing a positive change in behavior or mood.All the studies summarized focused on detecting behavioral changes in patients. This leaves opportunities to innovate with the data to actuate the detected behaviors using reinforcement learning approaches. Particularly, if a state of behavior is predicted before it visibly manifests, there is an opportunity to alert responsible adults nearby to intervene using proven interventions. Such timely interventions may prove to be a positive reinforcement for children, who otherwise are penalized for unacceptable behavior. In older patients , physiology-based triggers  with an action message  demonstrate promise in the diagnosis and prediction of aspects of disorders spanning child and adolescent psychiatry. Second, analytic solutions using data from wearables and expert annotations of child behavior can predict the onset of behavioral changes relevant to psychiatric disorders. Hence, given the growing ubiquity of wearables across the age span , our review strongly suggests the incorporation of wearables in child and adolescent psychiatry research. Such integration would be pivotal in facilitating remote monitoring and remote psychiatric services, which will likely help reduce disparities in mental health care access because of a shortage of child and adolescent psychiatrists. From a research perspective, the interaction of wearable biomarkers with conventional biomarkers  in the context of the diagnosis, treatment, and management of psychiatric disorders is yet to be pursued in large studies. Finally, the integration of wearables in child and adolescent psychiatry research should extend beyond controlled research settings to allow the extraction of the benefits of AI approaches. Naturalistic studies should look to collect annotations of children’s behavior as observed in their daily life at home, day care, or school and expand the involvement of relevant stakeholders in studies, wherein not only are parents annotating behaviors but also teachers, social workers, and counselors. Such a collection of annotated data from a real-world environment where children and adolescents develop will also provide opportunities to innovate with AI approaches such as reinforcement learning. Future directions should focus specifically on enrolling larger number of more diverse groups of patients. Future research should also focus on assessing which tools, mobile and wearable, are most efficient in collecting the most reliable data in various patient populations, as the primary outcome of interest.


Human Immunodeficiency Virus (HIV) infection continues to have a profound humanitarian and public health impact in western and central Africa, a region that risks being left behind in the global response to ending the AIDS epidemic. In Liberia, where the health system is being rebuilt following protracted civil wars and an Ebola virus disease outbreak, the Resilient and Responsive Health System (RRHS) is assisting with quality HIV services delivery through support from PEPFAR and HRSA but gaps remain across the cascade of care from diagnosis to viral load suppression.To highlight gaps in HIV service delivery in Liberia, identify opportunities and offer recommendations for improving the quality of service delivery.A narrative review of relevant literature was conducted following a search of all local and online databases known to the authors.Antiretroviral therapy (ART) has transformed the HIV response in Liberia by averting deaths, improving quality of life, and preventing new HIV infections but critical gaps remain. These include weak HIV prevention and testing strategies; suboptimal ART initiation and retention in care; low viral load testing volumes, commodity supply chain disruptions and a HIV workforce built on non-physician healthcare workers. In the context of the prevailing socioeconomic, heath system and programmatic challenges, these will impact achievement of the UNAIDS targets of 95-95-95 by 2030 and ending the epidemic.Combination prevention approaches are necessary to reach the most at risk populations, while a robust health workforce operating through facilities and communities will be needed to reach people with undiagnosed HIV earlier to provide efficient and effective services to ensure that people know their HIV status, receive and sustain ART to achieve viral suppression to maintain a long and healthy life within the framework of overall health system strengthening, achieving universal health coverage and the sustainable development goal. The Joint United Nations Program on HIV/AIDS (UNAIDS) estimated that 38 million people worldwide were living with HIV at the end of 2019, with 25.7 million of those residing in sub-Saharan Africa [1While there have been remarkable scientific and programmatic advances in HIV treatment and prevention, a cure remains elusive, and despite valiant efforts by public health authorities such as the World Health Organization, Global Fund for AIDS, Tuberculosis and Malaria, as well as the US President’s Emergency Plan for AIDS relief that have formed the backbone of policy, guidelines and resources for AIDS care in Africa, too many people with HIV or at risk for HIV still do not have access to prevention, care, and treatment. Beyond the health effects of HIV, the epidemic has wide ranging negative impact on households, communities, and economies of countries in the world that can least afford to deal with the public health threat . Many ofThe HIV prevalence in Liberia ranges from 1.5% to 2.1% among people 15–49 years of age 4. HIV pre5Figure 1).In an Integrated Biological and Behavioral Surveillance Survey (IBBSS) from 2013, the most at-risk population was MSM (19.8%), followed by female CSW (9.8%), Uniform services personnel (5.0%), transport workers (4.8%) and mobile traders (4.5%), injection drug users (3.9%) and miners (3.8%) 7  was the primary organization established in year 2000 to coordinate, monitor and mobilize resources for Liberia’s response to HIV and AIDS. Its mandates included promoting the active involvement of the private and public sector, in implementing HIV and AIDS services in Liberia. More recently, the Ministry of Health (MoH) through the National AIDS and Sexually Transmitted Infection (STI) Control Program (NACP) in collaboration with implementing partners (IPs) like the Resilient and Responsive Health System (RRHS) program partners and working with all County Health Teams (CHTs) are responsible for ensuring the provision of HIV services and adherence to National guideline for people living with HIV (PLWH) . Based oIn 2014, the Joint United Nations Program on HIV/AIDS (UNAIDS) announced an ambitious FastTrack strategy to end AIDS as an epidemic by 2030. In the strategy, a 95-95-95 target was set, whereby, 95% of PLWH should know of their status, of these, 95% should be on antiretroviral therapy (ART), and 95% of people on treatment should have a fully suppressed viral load by 2030 , these t8Priorities for effective HIV service delivery have been grouped, according to the HIV care cascade, into: optimizing HIV testing, linkage from HIV testing to care; initiating antiretroviral therapy (ART); supporting adherence, retention, and reengagement in care as necessary; managing advanced HIV disease and its complications (AHD); access to viral load testing, comprehensive chronic disease care and service integration 18. Howev9Figure 2) are a sine qua non for overall health system strengthening [20In the face of the aforementioned challenges, to achieve resilience in HIV service delivery in Liberia, necessary components include: robust funding, guideline development in a national context for HIV testing services (HTS) and ART coverage, laboratory capacity and services, community engagement, supply chain management for drugs, testing supplies and commodities, addressing existing HIV inequities among subpopulations, eliminating stigma, data management systems and partners collaboration . In addigthening 2021.In the last five years, overall domestic healthcare spending including for HIV services in Liberia has dropped . FundingDespite resource and capacity challenges, certain programmatic successes and challenges are worth highlighting. HIV prevention, testing and treatment is based on WHO recommendations but adapted and contextualized to the Liberian setting 25 HIV teConcerning community involvement and mobilization, task shifting of HIV-related services to community health assistants/workers (CHA/Ws) and PLWH network at the county level has been laudable but remain not fully integrated into the national testing and community ART distribution strategies  and disb27Timely and optimal HIV testing is the gateway to treatment with lifelong ART, preserving and prolonging life and decreasing community viral load (VL) to achieve epidemic control . KnowledOver the years, HIV testing sites have increased in Liberia but despite this improvement, challenges with delivering a high-quality HIV testing service remain. Uptake of HIV counselling and testing (HCT) is suboptimal and networks of PLWH are not actively engaged with testing outside of health facilities . Within 30Though community and facility based HTS is free in Liberia, the testing volume in 2018 was 269,426 with a positivity rate of 3.1% . These f32Effective combination antiretroviral therapy (cART) has resulted in significant reduction in HIV-related morbidity and mortality, near-normal life expectancy among PLWH, as well as preventing new HIV transmission . The num16Generic fixed dose combination ARVs in Liberia are made available through HIV programs by The Global Fund to Fight AIDS TB and Malaria (GFATM) and PEPFAR after WHO prequalification 36. Despi78The National AIDS Control Program, in 2019, in line with WHO guidelines 25, transWhile treatment availability and utilization have improved, there remains a significant challenge in the diagnosis and management of people presenting with advanced HIV disease (AHD), largely due to limited availability of diagnostics and treatment options for these preventable complications . ExampleSupply chain management, a critical piece of ART availability is being improved in Liberia. The USAID Global Health Supply Chain Program-Procurement and Supply Management (GHSC-PSM) project works with the Liberian National Drug Service (NDS) and Central Medical Store (CMS) to improve the availability of and access to life-saving HIV commodities . PrioritAchieving the individual and public health benefits of the UNAIDS 95-95-95 targets ultimately hinges on achieving the third 95 – community-wide viral load suppression . The sin42In 2013, the World Health Organization (WHO) recommended viral load testing six months after initiation of ART and every 12 months afterwards to detect treatment failure (defined as HIV RNA VL >1000 copies/mL on two consecutive measurements at least three months apart), and to guide switching to second line ART . The gui4546In 2020 following a needs assessment at one of the large volume ART site – John F Kennedy Medical Center (JFKMC) in Monrovia, a memorandum of understanding (MoU) was developed between the NACP, Partnership for Research on Vaccines and Infectious Diseases in Liberia (PREVAIL) and JFKMC to create access to GeneXpert platforms and other research infrastructure . This syRecently, education of PLWH has increased the awareness and created a demand for VL testing in the Liberian HIV program. However, with the absence of electronic health records (EHR), medical records and data management within the HIV program are still paper based, requiring cumbersome clinical processes to trigger or predict due dates for VL testing. Timely availability, reliability and completeness of data has created challenges with improving the VL testing processes and continuous quality improvement (CQI). Observational evidence across HIV programs in sub-Saharan African suggests that VL testing rate is better among countries with EHR systems. On-site phlebotomy, absent in Liberia HIV programs, may also improve testing rates . There aFalling short of the UNAIDS targets for 2020 , all sta19Under the leadership of the MoH and the NAC, a Fast-Track plan for 2019–2020 was developed that identifies high-impact programs, and barriers that must be removed to ensure better service delivery. It also recognizes that prevention measures must be escalated and that stigma and discrimination must be reduced .Innovative combination approach to HIV prevention that includes behavioural, biomedical and structural approaches and tailored to those in greatest need are needed to reach people with undiagnosed HIV earlier and improve the first 95. Budgets for condom and social marketing programs should be reinstated targeting a new generation of sexually active young people that have not been exposed to the intense condom promotion that was in place a decade ago in view of the prevailing poor knowledge of combination prevention  and the 50The Liberia catch-up plan seeks to triple the country’s test and treat figures and link people with positive tests to prompt treatment. Traditional testing strategies should be combined with newer testing strategies like the HIV self-testing and universal testing. The catch-up plan will be guided by a location–population approach, with a service delivery bias towards the three counties of Montserrado, Margibi, and Grand Bassa with the highest unmet need for HIV testing, treatment and care services, urban areas and some other locations with a focus on adults aged 15–49 years, pregnant women, MSM, commercial sex workers, people who inject drugs, prisoners, mine workers and other men – declared by UNAIDS as a “HIV blind spot” who traditionally have poor uptake of testing and other HIV services .Rapid ART initiation with newer and potent medications like DTG within seven days of HIV diagnosis including same day ART initiation will lead to improved retention in care and increased viral suppression 52. ConceThere is need to strengthen the frequency of training and continuing professional development (CPD) for health workers in the counties on advances in HIV care. Content should be tailored to target priority areas like task sharing protocols with clear roles and responsibilities delineated to guide clinical care and create clear pathways for physician oversight or referral especially with pediatric ART, elderly patients, newly diagnosed cases, adverse drug reactions, switching to second or third line ART, managing NCDs, inpatient care and AHD care . Other pThere is emerging evidence that ART can be successfully and safely started outside of health facilities following community-based testing . This apIn 2016, WHO recommended providing three to six months multi-month dosing (MMD) for stable clients to reduce the frequency of clinic visits and ART refills . This apThere are multiple reasons for suboptimal adherence, disengagement from care and loss to follow up. A combination of supportive interventions including use of peer or lay counselors, participation in adherence clubs, use of mobile text messaging and reminders are useful to support adherence and retention in care 325. Afte3Because of health workforce shortages, the Liberian HIV program is built on non-physician health care providers. There are existing gaps in delivering quality management of AHD and NCDs and this must be prioritized. Task sharing protocols must be enhanced to create clear and timely referral pathways that FastTrack and connect PLWH with AHD to physicians for inpatient care especially within the high volume and tertiary facilities like JFKMC and RDH where specialist physician providers are available. Funding should be provided to procure CD4 tests, GeneXpert platforms for HIV VL, urinary LAM and Serum CrAg to deliver the WHO minimum package of care for AHD . ScreeniBeyond routine reporting of HIV data to the health information management systems, effort should be made to enhance and capture good quality data from routine programmatic activities for quality improvement and research . A good Despite the existing gaps and challenges with the health system and HIV service delivery in Liberia, opportunities abound to improve quality of care towards achieving the 95-95-95 targets by 2030. This would require coordination, commitment and resolve of all stakeholders–health care providers, program managers, international partners/donors and government–to provide resources, implement programs and adopt innovative solutions to address the many opportunities highlighted. Once accomplished, PLWH in Liberia will achieve the so called fourth “90”–to live a long and healthy life and collectively achieve epidemic control.