Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment but are associated with significant autoimmune endocrinopathies that pose both diagnostic and treatment challenges. The aim of this guideline is to provide clinicians with the best possible evidence-based recommendations for treatment and follow-up of patients with ICI-induced endocrine side-effects based on the Grading of Recommendations Assessment, Development, and Evaluation system. As these drugs have been used for a relatively short time, large systematic investigations are scarce. A systematic approach to diagnosis, treatment, and follow-up is needed, including baseline tests of endocrine function before each treatment cycle. We conclude that there is no clear evidence for the benefit of high-dose glucocorticoids to treat endocrine toxicities with the possible exceptions of severe thyroid eye disease and hypophysitis affecting the visual apparatus. With the exception of thyroiditis, most endocrine dysfunctions appear to be permanent regardless of ICI discontinuation. Thus, the development of endocrinopathies does not dictate a need to stop ICI treatment. Over the past decade, immune checkpoint inhibitors (ICI) have revolutionized oncological treatments. These drugs are monoclonal antibodies targeting specific cell surface molecules (checkpoints) present on various cell types of the immune system that harness immune reactions. By releasing these endogenous immunological breaks, immune recognition and destruction of cancer cells can take place. In highly aggressive cancers such as malignant melanoma and lung cancer, ICI treatment has led to dramatically increased survival , 2, 3. HAt present, the two most frequently targeted immune checkpoints are the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) . CTLA-4 The first ICI registered for human use was ipilimumab, an anti-CTLA-4 antibody, approved for metastatic melanoma in 2011 . Since tAt present, the CTLA-4 inhibitor ipilimumab; PD-1 inhibitors nivolumab, pembrolizumab, and cemiplimab; and PD-L1 inhibitors atezolizumab, avelumab, and durvalumab are FDA- and EMA-approved. The main fields of their usage are summarized in Supplementary Table 1  thyroid-stimulating hormone (TSH), free thyroxine (fT4), cortisol (with attention to any recent or current glucocorticoid treatment), glucose, and electrolytes . These tests should be repeated every 4–6 weeks, preferably before each treatment cycle starts.Comprehensive baseline assessment: Morning (8:00–9:00 h) adrenocorticotropic hormone (ACTH), luteinization hormone (LH), follicle-stimulating hormone (FSH), estradiol , testosterone , prolactin, and glycated hemoglobin (HbA1c).The baseline minimum tests should be performed in all patients and the comprehensive tests should be used when there is an increased risk for hypophysitis, for instance, when ipilimumab is used alone or in combination with a PD-1 inhibitor. For the diagnosis of specific endocrinopathies, additional tests may be indicated as suggested in each sub-section below.This guideline was developed on behalf of The European Society of Endocrinology (ESE), the chairs of the working group, Eystein S. Husebye and Olaf M. Dekkers were appointed by the ESE Clinical Committee. Olaf M. Dekkers served as methodological expert, Maria Fleseriu as representative of The Endocrine Society, USA, Sherwin Criseno as ESE Nurses Representative, Stavroula A. Paschou as ESE Young Endocrinologists and Scientists representative, and Guiseppe Curigliano as The European Society for Medical Oncology representative. The other members were suggested by the chairs and approved by the Clinical Committee of ESE, including Claire Higham, Brigitte Decallonne, Fredric Castinetti, Miklos Toth, and Isabella Lupi. Monique van der Kooij joined the guideline working group for methodology support. Due to COVID restrictions, all three working group meetings were held virtually and further communication was done by email. Consensus was reached upon discussion; minority positions were taken into account in the rationale behind recommendations. Prior to the process, all participants completed conflict of interest forms.This guideline was developed for health care professionals who may see patients with endocrine-related adverse conditions during or after ICI treatment and who seek guidance for the treatment and follow-up. General practitioners, nurses, and patients might also find the guideline useful. The guideline can serve as a source document for the preparation of patient information leaflets and educational materials.The purpose of this guideline is to provide clinicians with practical guidance on the management of patients with ICI-related endocrine conditions. In clinical practice, both the recommendations and the clinical judgment of the treating physician should be taken into account. Recommendations are not meant to replace clinical acumen and may need adaptation to local circumstances.+000), low (++00), moderate (+++0), or strong (++++). Not all recommendations were formally graded (see below).The methods used for establishing the guideline have been described in detail previously . In shorFor the recommendations, we considered the quality of the evidence, the balance of desirable and undesirable outcomes, and individual values and preferences  , 26. TheAt the start of this guideline process, the committee members formulated clinical questions regarding treatment and follow-up of ICI-related endocrine conditions. The clinical questions that formed the basis of the systematic literature search and review are summarized in Supplementary Table 2.Cohort studies assessing the prevalence and treatment of ICI-related endocrine adverse events in patients with cancer who received ICI were eligible for inclusion. Eligible studies included adult patients (>18 years old). All cancer subtypes were eligible, for which treatment with ICI was approved by the FDA and EMA. ICI treatments included: anti-CTLA-4 (ipilimumab), anti-PD-1 , anti-PD-L1 , and combination treatment of ipilimumab and nivolumab. Combination treatment with ICI and chemotherapy or ICI with targeted therapy was not considered. Only studies reporting on ten or more patients were considered eligible in order to avoid selection bias. Eligible studies were restricted to languages familiar to the authors.The following endocrine adverse conditions related to ICI treatment were considered: hypophysitis, thyroid disorders , adrenal insufficiency, diabetes mellitus, hypoparathyroidism, and polyendocrine syndromes. Interventions were divided into three different categories: (i) pharmacological glucocorticoid treatment for management of the endocrinopathy , (ii) hormone replacement therapy  or anti-thyroid drugs, and (iii) dose modification, holding, or discontinuation of ICI treatment. The control was defined as no intervention or best supportive care. In addition, studies without interventions were considered for information on the natural course of the endocrinopathy. Outcome measures were recovery from the adverse event, ongoing or permanent organ dysfunction, hospitalization, and adverse event-related mortality. Details of included studies are shown in Supplementary Table 3, the GRADE assessment in Supplementary Table 4.In October 2020, PubMed, EMBASE, EMCARE, Web of Science, and COCHRANE Library were searched to identify potentially relevant studies, published since the introduction of ICIs in clinical practice in 2010. All studies obtained from this search strategy were entered into reference manager software  and screened for title and abstract. Potentially relevant studies were retrieved for detailed assessment.A draft of the guideline was reviewed by four experts in the field (see ‘Acknowledgments’ section) and was distributed to all ESE members for comments. In addition, the following societies and networks were asked to review the guidelines; Endocrine Society, International Endocrine Society, and European Society for Medical Oncology. All comments and suggestions were then discussed and implemented as thought appropriate by the panel.Based on a group consensus, we arrived at the following general recommendations:R 1.1 - We recommend that a controlled endocrinopathy is not a contraindication for initiation and/or continuation of ICI therapy (++00).Rationale:The oncologic benefit of ICI treatment outweighs the risk related to ICI-induced endocrinopathies, in almost all instances. Rare cases  may need endocrine control first, but this can be done within days to weeks and should not stop or delay treatment with ICI significantly. Several studies have reported on the safety and efficacy of ICI treatment in patients with pre-existing autoimmune diseases. A recent cohort study including 143 metastatic melanoma patients with a pre-existing endocrine autoimmune disease (mostly thyroid) showed that these patients neither develop more endocrine-related CTCAE grades 3–4 adverse events following ICI nor did they have a lower response rate or survival .Rationale: Endocrine conditions listed other than primary hypothyroidism are usually cared for by an endocrinologist. They are chronic lifelong conditions with long-term complications if not treated properly.R.1.4 - We recommend that patients with ICI-induced endocrine dysfunctions are provided with adequate education and training on effectively managing their conditions including provision of appropriate verbal and written instruction on how to adjust their medications during periods of illness.The overall incidence of hypophysitis is up to 17% in patients treated with ICI; with a female: male ratio of 1:4. The mean age at onset is approximately 60 years and mean time to onset is 10.5 weeks for CTLA-4 inhibitors and 27 weeks for PD-1/PD-L1 inhibitors . The preICI-induced hypophysitis has several distinctive features compared with autoimmune (primary) hypophysitis. The former is more common in males, presents at an older age, and almost always with symptoms and signs of hypocortisolism, whereas manifestations related to pituitary enlargement are overall moderate , 35, 36.Pituitary antibodies assayed by indirect immunofluorescence on human pituitary sections were found in 15 out of 17 (88.2%) and 4 out of 5 (80%) patients treated with anti-PD1 or anti-CTLA-4, respectively . The pitClinical presentations of hypophysitis vary depending on ICI type and dose. In anti-CTLA-4-induced hypophysitis, ACTH deficiency is most common (95%) and is often accompanied by other pituitary insufficiencies . SecondaPrior to evaluating pituitary function, any concomitant use of drugs that may interfere with pituitary function or with hormone assays should be identified. Screening for pituitary dysfunction should be done as per current guidelines . NotablySeven observational studies have been published studying pituitary insufficiency in patients after ICI treatment , 46, 47.R 2.1 - We recommend the use of high-dose glucocorticoids in case of an acutely unwell patient ICI-treated with suspected adrenal crisis, more specifically 100 mg hydrocortisone intravenously or intramuscularly followed by 50 mg every 6 h and fluid resuscitation Rationale:There is currently no evidence for the efficacy of high-dose glucocorticoid treatment, and there may actually be an increased mortality risk with this approach .Rationale:Use of doses equivalent to 7.5 mg prednisolone or higher for more than 3 weeks can lead to secondary adrenal insufficiency. Thus, at least a medication fasting morning cortisol (plus ACTH) and if needed a 250 µg Synacthen® test should be considered if glucocorticoids are considered to be stopped. The decision to taper the glucocorticoid dose and assess the HPA axis will depend on the prognosis of the patient. In patients with confirmed adrenal insufficiency on glucocorticoid replacement therapy, there is no indication for routine assessment of cortisol levels.R 2.5 - We recommend thyroid hormone replacement therapy in patients with hypophysitis who have decreased or low-normal fT4 .Rationale:As levothyroxine treatment can precipitate an adrenal crisis in a patient with untreated adrenal insufficiency, adrenal insufficiency should be excluded and glucocorticoids initiated when needed, prior to the start of levothyroxine. TSH cannot be used to monitor dosing in central hypothyroidism. It is therefore common to give a replacement dose that puts fT4 in the upper part of the reference range .Rationale:Recovery of thyroid axis has been reported, this may indicate a resolution of central hypothyroidism, recovery of non-thyroidal illness or because other medications affected thyroid function tests  ( agents) , 39, 53.R 2.7 - We suggest not to directly correct gonadal dysfunction in the setting of a poor oncologic prognosis .Rationale:Suppression of the gonadotrophins axis by illness and treatment is common and should preferably be resolved before sex steroid replacement is considered. Furthermore, the age of the patient and oncologic prognosis must be taken into consideration. Since there are reports of reversibility of secondary hypogonadism, sex steroid replacement – when initiated – should be short term and evaluated again before long-term treatment is considered.R 2.8 - We suggest replacing gonadal hormones, with testosterone in men and estrogen and progestagen in women of reproductive age, in the setting of hypophysitis with persistent and confirmed hypogonadotropic hypogonadism .Rationale:For women, sex steroid replacement during reproductive age is important for well-being and to prevent complications such as osteoporotic fractures and cardiovascular disease. It is common to continue replacement to the age of normal menopause around 50 years of age. Consider transdermal estrogen administration to minimize thromboembolic risk. For men, testosterone is important for well-being, libido, bone health, muscle strength, and to avoid anemia. In the absence of any contraindications  or increased risk of acute thromboembolic complications, a decision with regards to gonadal replacement should be guided by the patient’s age, symptomatology, cancer type, and prognosis. Osteoporosis should be treated with calcium and vitamin D supplementation and bone-directed agents, if sex steroid replacement is not feasible.R 2.9 - We recommend against treating GH deficiency in patients with hypophysitis in the presence of an active malignancy.Rationale:Although GH deficiency in the long term can affect morbidity, GH replacement therapy during malignancy, as in patients with ICI-induced hypophysitis, is contraindicated .Rationale: Desmopressin is needed to maintain normal osmolality and sodium concentration. Other causes of sodium imbalances should be considered. Aldosterone deficiency causes urinary sodium loss and cortisol deficiency impairs free renal water clearance. These conditions may mask the presence of central DI and must be corrected before testing for vasopressin deficiency. In a patient with polyuria (defined as urine output of more than 50 mL/kg/24 h), after exclusion of adrenal insufficiency and diabetes mellitus, serum and urine osmolarity are measured. Other causes, such as renal dysfunction, hypokalemia, or hypercalcemia, and the effects of diuretics should also be considered. In the presence of high serum osmolarity (above 295 mOsmol/L), a urine osmolality/serum osmolality ratio of two excludes the diagnosis of DI  .Rationale: Adrenal crises and poorly controlled DI can be avoided and/or alleviated by early treatment started either by the patient or a relative who has received education in these conditions. Thus, self-management should include training on stress dosing (‘Sick Day Rules’), self-administration of hydrocortisone injection in the event of an emergency and provision of appropriate resources  to enable accurate communication of their conditions and treatment with other healthcare professionals. Consider referral to a patient support group (if available) for ongoing peer-support.Thyroid dysfunction represents the most common ICI-related endocrine adverse event. Anti-PD-1/PD-L1 treatment carries a higher risk than anti-CTLA4 treatment, with the highest risk for combined treatment . Most ca18F-deoxyglucose uptake in the thyroid , following myasthenia gravis (45%), orbital myositis (14%), and optic neuritis (13%). Six out of ten cases were associated with Graves’ disease. Thyroid eye disease developed typically 2–4 months following initiation of ICI. Peroral or i.v. high-dose glucocorticoids were used in nine out of ten patients. ICI was held or terminated in the majority, while it was continued in three patients. Improvement or resolution was reported in all but one patient, even in two out of three patients with continued administration of ICI . The verAs thyroid dysfunction is mild in the majority of cases, diagnosis relies on the combined measurement of TSH and fT4, also allowing the detection of central hypothyroidism. When thyroid dysfunction is overt, symptoms and signs should not be confounded with those related to the underlying malignant disorder or other side-effects of ICI treatment. Furthermore, thyroid tests can be influenced by other factors, such as drugs, non-thyroidal illness, and iodine-based contrast agents. All guidelines advise screening of thyroid function prior to the initiation of ICI, but it is generally not recommended to screen for TPO-antibodies , 19, 78.During ICI treatment, it is generally advised to monitor TSH and fT4 prior to every ICI treatment cycle during the first 6 months, after which the interval can be prolonged to every 2–3 months for 6 months and every 6 months thereafter. In case of discrepant test results or non-concordance between clinical and biochemical findings, assay interference should be suspected . In caseMost cases of thyrotoxicosis can be treated with beta-blockers for symptomatic relief. Graves’ disease requires treatment with anti-thyroid drugs. Primary hypothyroidism is treated with levothyroxine aiming at normalisation of TSH values.Eight studies reporting on levothyroxine replacement therapy could be included in our systematic review , 82, 83.A retrospective analysis of high-dose glucocorticoid treatment of ICI-related thyroid disorders (15 patients treated vs 38 patients not treated with high-dose glucocorticoids) concluded that glucocorticoids did not prevent or reduce ICI-induced thyroid damage. There was no difference in maintenance dose of levothyroxine between patients receiving high-dose glucocorticoids  and those who did not , nor in time to onset of thyrotoxicosis, time to conversion to hypothyroidism, or time to onset of hypothyroidism . HoweverR 3.1 - We recommend against the use of high-dose glucocorticoids for the treatment of thyroiditis; except in severe thyrotoxicosis and severe thyroid eye disease (+000).Rationale:There is no evidence for treatment efficacy of high-dose glucocorticoid therapy. Moreover, such treatment can induce secondary adrenal insufficiency if doses of prednisolone > 7.5 mg per day are given for longer than 2–3 weeks. In cases of severe thyrotoxicosis, high-dose glucocorticoids reduce T4 to T3 conversion. Cases of ICI-related thyroid eye disease are extremely rare but can occur even in the absence of increased TSH receptor-antibodies and should be referred to an endocrinologist and ophthalmologist for shared decision regarding treatment with high-dose glucocorticoids.R 3.2 - We suggest that cases of clinically and biochemically mild thyrotoxicosis or hypothyroidism can be monitored without treatment .Rationale:Most cases of thyroid dysfunction are mild. Monitor TSH and fT4 every 3–6 weeks in the early phase; the frequency can be lowered at later stages  ( trends) .R 3.3 - We recommend using beta-blockers in symptomatic thyrotoxicosis .Rationale:Short-term treatment with a non-selective beta-blocker (e.g. propranolol) can be initiated to resolve symptoms of thyrotoxicosis. As most cases are caused by thyroiditis, anti-thyroid drugs are not indicated, except in rare cases of Graves’ hyperthyroidism, which should be referred to an endocrinologist for shared care. Radioactive iodine and thyroid surgery are not recommended as first-line treatment of ICI-related thyrotoxicosis.R 3.4 - We suggest replacement with levothyroxine in primary hypothyroidism in cases with fT4 below the lower reference limit and TSH > 10 mIU/L. (++00)Rationale:Symptoms and signs of hypothyroidism are difficult to evaluate in an oncological setting, but in cases of overt hypothyroidism, we recommend replacement as there is a significant chance of clinical improvement. A starting dose of 1.0 µg/kg/d (25 µg/d in elderly or in patients with cardiovascular comorbidity) is appropriate. Regular monitoring of thyroid hormones (TSH and fT4) is needed in order to titrate levothyroxine dosage at intervals of at least 6 weeks. In patients with low-dose replacement, we suggest considering tapering and stopping levothyroxine periodically to assess whether thyroid function has recovered (+000)R 3.5 - We recommend against routine replacement with levothyroxine of ICI-treated patients with a TSH between 4–10 mIU/L and a normal fT4 (+000).Rationale:The decision depends on the level and trend of fT4 and symptoms. Regular monitoring of thyroid tests (TSH and fT4) and timely balancing of the benefit/risk ratio of initiating levothyroxine replacement are needed.R 3.6 - In case of ICI cessation, ongoing monitoring of thyroid function (TSH and fT4) is still indicated, albeit less frequently (e.g. every 6–12 months and in case of symptoms and signs of thyroid dysfunction).Rationale:Thyroid dysfunction can develop at a later stage and symptoms are usually non-specific. Ongoing biochemical testing is therefore needed for at least two years  ranges from 0.9 to 2%. There is a female to male ratio ranging from 1:1.2 to 1:9, and a mean age at onset of over 60 years , 87, 88.When hyperglycemia is present, urine ketone testing and blood pH measurement are recommended for early diagnosis of diabetic ketoacidosis (DKA). Use of SGLT2-inhibitors is an additional risk factor for DKA . HbA1c iTwo studies were included in our systematic review, both showing that insulin treatment is mandatory for patients with DM following ICI treatment with  no chance of subsequent insulin withdrawal , 92. TheR 4.1 - We recommend that patients presenting with DKA should be managed with i.v. insulin and fluid resuscitation according to current guidelines .Rationale:ICI-induced DM typically develops rapidly with profound lack of insulin. There is no evidence that high-dose glucocorticoids rescue beta cell function. High-dose glucocorticoids will also increase serum glucose substantially.R 4.3 - We recommend treating ICI-induced persistent DM due to islet destruction with s.c. insulin (++00).Rationale:Islet destruction leads to severely reduced insulin secretion. Thus, standard treatment mode is a multiple insulin injection regimen. Age, overall prognosis, and the patient’s abilities should be taken into account when planning the treatment, and target HbA1c should be individualized. The probability of spontaneous recovery is low. There is no evidence that high-dose glucocorticoids will reverse ICI-induced DM.R 4.4 - We do not recommend routine complication screening in the first years after the development of ICI-induced DM, taking into account age and prognosis.Rationale:Since ICI-induced DM develops rapidly, we can assume that there are no long-term complications at diagnosis, but we suggest that patients are entered into a screening program. If type 2 DM is suspected, we suggest to include the patient in the regular screening program for complications.R 4.5 - We recommend that patients with DM are provided with appropriate and regular training on managing their condition and treatment, including diet and physical activity .Rationale: The patients need the same education in self-management as patients with type 1 DM.Primary adrenal insufficiency is a rare complication of ICIs, and to date, only few cases have been presented in the literature, making an estimate of incidence very difficult , 94. A rEvidence for an underlying autoimmune association has been documented after the use of PD-1 and PD-L1 inhibitors, including atezolizumab , pembrolDiagnosis of primary adrenal insufficiency follows the Endocrine Society guidelines . Often aThere are no studies on ICI-induced adrenal insufficiency and its treatment of good quality. One study reported on ten patients with adrenal insufficiency (3.5% of the full cohort); one patient was suspected to be in the early stages of empty sella syndrome, and all other patients were either confirmed or suspected of having secondary adrenal insufficiency (see Supplementary Tables for details). Albeit four patients also showed adrenal metastases on imaging . All patR 5.1 - We recommend against the use of high-dose glucocorticoids for treatment of primary adrenal insufficiency (+000).Rationale:There is no evidence for treatment efficacy and high-dose glucocorticoid pose a risk of inducing secondary adrenal insufficiency.R 5.2 - We recommend standard glucocorticoid replacement therapy for patients with proven primary adrenal insufficiency .Rationale:There are no reported spontaneous recoveries after cessation of ICI. If we assume that ICI-induced adrenal insufficiency is caused by the same mechanisms as regular autoimmune adrenal insufficiency, reversibility is very rare although residual adrenocortical function has been reported .Rationale:There is no evidence of spontaneous recovery after cessation of ICI therapy. Since destruction of the adrenal cortex causes a lack of aldosterone, replacement therapy with fludrocortisone (0.05–0.15 mg) and a diet without salt restriction is recommended. Hydrocortisone and cortisone acetate have some mineralocorticoid effect, prednisolone less so. Thus, a slightly higher mineralocorticoid dose might be needed (e.g. by 0.05 mg) if the patient is switched to prednisolone compared to hydrocortisone and cortisone acetate.R 5.4 - We recommend against stopping glucocorticoid and/or mineralocorticoid replacement abruptly without formally checking adrenal function, even if the ICI was stopped .Rationale:As there is no evidence of recovery, it is essential that adrenal function is checked before corticosteroids are stopped. We recommend the standard 250 µg synacthen test and test of aldosterone and renin levels.R 5.5 - We recommend that patients with primary adrenal insufficiency are provided with appropriate and regular training on managing their glucocorticoid treatment during period of illness (‘Sick Day Rules’) .Rationale: Adrenal crises can be avoided and/or alleviated by early treatment started either by the patient or a relative who has received education in these conditions. Thus, self-management should include training on stress dosing (‘Sick Day Rules’), self-administration of hydrocortisone injection in the event of an emergency and provision of appropriate resources  to enable accurate communication of their conditions and treatment with other healthcare professionals. Consider referral to a patient support group (if available) for ongoing peer-support.et al. indeed recently showed in a series of 178 patients treated with nivolumab, pembrolizumab, or ipilimumab that only one patient was actually presenting with hypocalcemia after correction for albumin , with undetectable or low-normal PTH levels. Electrocardiograms showed prolonged corrected QT intervals (between 481 and 493 ms) in the four cases in which it was reported.et al. reported PD-1 expression in 30% of 28 parathyroid carcinomas and 49% of 63 parathyroid adenomas. This might explain why the three cases of hypoparathyroidism occurred after use of at least one PD-1 ICI . Hypoparathyroidism occurred between 2 and 15 cycles of ICI. Most cases of hypoparathyroidism were irreversible. Interestingly, in one patient, hypocalcemia worsened despite the withdrawal of ICI. Even though the expression of PD-1/PD-L1 or CTLA4 is not known in normal parathyroid tissue, Pan PD-1 ICI . There aThe autoimmune nature of ICI-related hypoparathyroidism was based on finding activating calcium-sensing receptor (CaSR) autoantibodies in three cases , 108. A Hypercalcemia in patients under ICI has also been reported but seems to be non-PTH-mediated in the context of humoral hypercalcemia of malignancy or PTH-related peptide production. Recently, a case of calcitriol-mediated resistant hypercalcemia was reported in a patient treated with nivolumab . At presWhen hypocalcemia is detected, magnesium, phosphate, 25-OH-vitamin D, and PTH should be assessed.Only isolated case reports are available.R 6.1 - We recommend against the use of high-dose glucocorticoids for treatment of hypoparathyroidism in patients under ICI treatment; we recommend to give the same treatment as used in hypoparathyroidism due to other causes (++00).Rationale:The major goal is to correct symptomatic hypocalcemia and avoid short- and long-term complications related to hypoparathyroidism or its standard treatment  such as paresthesia, neuropsychiatric disorders, renal calcinosis  and full-length PTH .Rationale: Based on the frequency of polyendocrinopathy in regular organ-specific autoimmune diseases, it is to be expected that similar frequencies can occur in ICI-induced endocrinopathies. This is supported by a number of case reports.Patients who developed endocrine dysfunction during or after ICI treatment will likely require one or more lifelong hormone replacement therapies. Therefore, it is crucial that patients are provided with adequate training and support to effectively manage their condition and ensure continuity of safe care when they require acute care interventions. Effective self-management can be supported through provision of appropriate education, empowerment, and engagement activities.Comprehensive patient education is an essential element of toxicity management and high-quality cancer care. Enhanced awareness of the expected and possible adverse events improves coping skills and resilience in patients, leading to treatment adherence and improved health outcomes. For effective management of adverse effects, early recognition and treatment initiation are essential. Occurrence or worsening of new symptoms and signs should be reported immediately. Patients should avoid endocrine self-management without coordination with their multidisciplinary team, including an endocrinologist. Patients must also be informed that adverse events can occur at any time and even after ICI treatment arrest.Specifically, patients with cortisol deficiency should be educated on how to adjust their glucocorticoid treatment during period of intercurrent illness (‘Sick Day Rules’) and trained on the preparation and administration of glucocorticoid injection in the event of an emergency. They should wear a medical alert bracelet/necklace and carry a steroid alert card to communicate appropriate management in case of an adrenal crisis. We encourage that patients with adrenal insufficiency be referred to a patient support group (if available) for ongoing peer support.Patients with DM should be provided with appropriate and regular training on managing their diabetes including diet and physical activity and referred to a patient support group (if available) for ongoing peer support.ICIs have significant endocrine side-effects that physicians treating these patients need to know about, since they are relatively frequent, and their management differs from other immune-related adverse events in three key ways: (i) ICI therapy can be continued in most cases, (ii) high-dose glucocorticoids are rarely required for management, and (iii) endocrine deficiency usually persists, necessitating lifelong replacement, except for cases with transient thyroiditis.There is a surprising lack of reports on endocrinopathies related to ICI therapy in large patient databases which include data on adequately diagnosed ICI-induced endocrinopathies in patients followed up over time. As the range of ICIs is expanding, there is a need to establish registries with long-term follow-up, not only to register side-effects but also the outcome of oncologic and endocrine treatments.The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.European Society of Endocrinologyhttp://dx.doi.org/10.13039/100010382.The guideline was sponsored by the


Hip fracture is associated with substantial morbidity and mortality, especially among the elderly. Current evidence on the association between cigarette smoking and mortality in hip-fracture patients is controversial. We performed a systematic review and meta-analysis of studies on this association.2 statistic. Study quality was assessed by the modified Newcastle-Ottawa Scale (NOS) and publication bias was evaluated by a funnel plot, Begg’s and Egger’s tests. Subgroup analyses were performed by study design, race/ethnicity, age ≥60 years, smoking status, and follow-up period.The databases Medline/PubMed, Embase, Web of Science, and Cochrane Library were searched for studies that estimated the effect of smoking on the risk of mortality in hip-fracture patients. Pooled analyses were conducted of the associations, expressed in relative risk (RR) and 95% confidence intervals (CIs). Heterogeneity was assessed using the IA total of six articles involving 3739 hip-fracture patients were included in the meta-analysis. Our results indicate that ever-active smoking was significantly associated with an increased risk of death in hip-fracture patients . In further subgroup analysis, the risk of death was significantly higher in ever-active smokers than in never smokers in White participants  and elderly aged ≥60 years , with no significant association in Asian participants . Current smokers had more risk of death than never smokers . The association was significant in follow-up periods of ≤1 year , 3 years , and 5 years .Cigarette smoking is associated with an increased risk of mortality in hip-fracture patients, especially in elderly patients aged ≥60 years, current smokers, and White participants. With the extension of follow-up period, the effect on mortality of smoking is profound and lasting. By the year 2040, the estimated annual healthcare costs will reach US$9.8 billion in the United States and $650 million in Canada4. This mortality rate has remained relatively stable over time, in contrast to declining mortality rates associated with other causes, such as acute myocardial infarction, underscoring the need to identify preventable risk factors of mortality following hip fracture. Studies showed smoking was associated with an increased risk of hip fracture6. Tobacco smoking is a global public health threat, especially among the youth and Asian populations7, and causes more than seven million deaths annually worldwide8. Furthermore, smoking-related diseases are associated with a huge economic burden to individuals and healthcare systems worldwide9. These diseases are estimated to contribute to about 5.7% of the global health expenditure. Smoking increases the incidence and mortality of various diseases, including cardiovascular and lung disorders12.Hip fracture has become a global public health problem associated with substantial mortality and heavy social economic burden. Mortality at 1 month after hip fracture is approximately 10%, and mortality within 1 year after hip fracture can reach 36%, despite aggressive management, including surgery and rehabilitation14, whereas others showed no positive association between the two factors18. To our knowledge, no systematic review and meta-analysis has demonstrated the association between cigarette smoking and hip-fracture mortality until now. Here, we performed one to assess the associations between the two factors.Currently, the association between cigarette smoking and hip-fracture mortality remains controversial. There have been conflicting views from different studies. Some researches demonstrated that cigarette smoking increased hip-fracture mortality19. The protocol for this meta-analysis is available in PROSPERO (CRD42022315017). All supporting data are available within the article and the Supplementary file.This meta-analysis was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines (PRISMA)Medline/PubMed, Embase, Web of Science, and Cochrane Controlled Register of Trials databases were searched to identify relevant studies evaluating the association between smoking and mortality of hip fracture published until 20 February 2022. The following MeSH terms were used for the search: 1) ‘hip fractures’ or ‘trochanteric fractures’ or ‘intertrochanteric fractures’ or ‘subtrochanteric fractures’; 2) ‘smoking’ or ‘smoker’ or ‘tobacco’ or ‘cigarette’; and 3) ‘prognosis’ or ‘predictor’ or ‘death’ or ‘mortality’ or ‘survival’. The search strategy is shown in Supplementary file Data 1. The references of the included studies were also screened.20; 3) articles reporting multivariate analysis effect estimates on the association between smoking and hip-fracture mortality. For studies based on the same data sources, the articles with the most complete data were included. Review articles, case reports and editorials were excluded.Studies were selected based on the following inclusion criteria: 1) articles published in English; 2) studies involving in patients with hip fractureSubjects were grouped into ever-active smokers and never smokers, and the risk of hip-fracture mortality was compared between these two groups. Ever-active smokers included current smokers who were smokers when participating in the study and former smokers who already quit smoking before the study period. We combined current and former smokers into one group in the main analysis because many studies did not separately report the estimates for current and former smokers. Never smokers were defined as those who never smoked before participating in the study. We compared the risks of hip fracture-associated mortality separately between ever-active smokers and those who never smoked. The study outcome was mortality in patients diagnosed with hip fracture.Two researchers independently screened the studies for title and abstract. The full text of relevant articles was retrieved. Study eligibility was assessed by checking the research questions, study design, data analysis, outcome, and data availability. Disagreements were resolved through discussions between the two researchers. Effect estimates of hip-fracture mortality with the corresponding 95% confidence intervals (CIs) were obtained from studies involving ever-active smokers. All the extracted effect estimates were recorded into a standard form. The following information was collected from the selected studies: year, mean age, cohort size, study design, target population, smoking status and definitions, outcome variables, and adjusted covariates.21. This 9-point scale assesses three types of biases: selection of study groups (4 points), comparability of cohorts (2 points), and ascertainment of exposure and outcomes (3 points). Quality was scored as: low (0–3), moderate (4–6), and high (7–9 points). Disagreements in the assessment were resolved by consensus. Quality ratings of the studies are shown in Two researchers independently assessed the quality of relevant studies. The quality of studies was evaluated using the Newcastle-Ottawa Scale (NOS)The analysis was stratified by smoking status and hip-fracture mortality, using a fixed-effects model when heterogeneity was low or random-effects model for high heterogeneity. Studies were excluded if the relative risk (RR) could not be calculated because of insufficient data or lack of data on CIs. When crude and adjusted hazard ratios (HRs) were reported, adjusted values were used.2 statistic22. This statistic describes the variance among studies as a proportion of the total variance. A value of I2<25% indicates low heterogeneity, 25–50% moderate, >50% to 75% high, and >75% very high heterogeneity. The associated p-value of the heterogeneity of the studies was also calculated, with a non-significant result indicating absence of heterogeneity. Subgroup analyses by study design, race/ethnicity, age ≥60 years, smoking status, and follow-up period, were performed.The heterogeneity of the studies was tested using the I23 and Begg’s test24 were used to statistically assess publication bias. Statistical analysis was conducted using Stata version 14.0. A p-value of less than 0.05 was considered statistically significant.Funnel plots of values of log RR and standard error were created to visually evaluate publication bias, and Egger’s regression test18 were included in the meta-analysis (Supplementary file Data 2).A total of 10997 relevant studies were retrieved. After removing duplicates, 10278 studies were screened. A total of 534 studies were excluded as these were meta-analyses, systematic reviews, reviews, case reports, and animal studies. Among 9744 eligible articles, 9636 were excluded after abstract screening. Of the remaining 108 studies, 102 were excluded because of irrelevant content (22), conference abstracts without reporting enough findings (23), lack of valuable data (48), and inappropriate outcomes associating smoking and mortality of hip fracture (9). Six studies15, and five were prospective18. The studies were performed in China (3)16, Iran (1)14, Australia (1)17, and Sweden (1)18, and were published between 2009 and 2021. The sample sizes ranged from 203 to 1944 participants. Five studies targeted populations aged ≥60 years18, and one targeted a population aged ≥50 years14. The follow-up period varied from 1 to 57 months. Most studies did not clearly define smoking, and some studies adjusted RRs for covariates.The characteristics of the selected studies are shown in Among the 6 included articles, 3 studies had a NOS score of 7, while the other 3 studies had a NOS score of 8. All studies displayed a NOS score of ≥6 .Primary analysis2=0.0%, p=0.605, fixed-effects model).The RRs for each study and the combined RR for ever-active smokers compared with never smokers are presented in Subgroup analysesSubgroup analysis by study design revealed a significant association between ever-active smoking and an increased risk of hip-fracture mortality in the prospective studies  (Supplementary file Data 3). Subgroup analysis by race/ethnicity showed a significant association in White participants , but no significant association in Asian participants  (Supplementary file Data 4). Significant association was also found in subgroup analysis by age  (Supplementary file Data 5) and current smokers  . FurtherPublication biasVisual evaluation of the funnel plots revealed a symmetrical distribution . Accordi3. The overall impact of smoking on the clinical manifestations of hip fracture is unclear. In this study, we presented the findings of our meta-analysis, which was aimed at evaluating the association between smoking and risk of hip-fracture mortality. Our findings indicate that smoking increases the mortality risk from hip fracture, especially in elderly patients aged ≥60 years, current smokers, and White participants. With the extension of follow-up period, the effect on mortality of smoking is profound and lasting. The issue with the association between smoking and hip-fracture mortality suggests the necessity of introducing smoking monitoring to the management of hip fracture and taking effective measures to promote no smoking to reduce mortality in these patients.Hip fracture is associated with approximately 10% mortality at 1 month and 36% mortality within 1 year, despite aggressive management25. The current study showed that comorbidities significantly increased the risk of mortality after hip fracture28. Malignancy was reported to be the highest risk factor for mortality in patients who underwent hip-fracture surgery29. Cardiovascular disease and pneumonia also increased the risk of death in these patients29. Individuals with chronic obstructive pulmonary disease (COPD) had a 60–70% higher risk of death following hip-fracture surgery than those without COPD30. Therefore, smoking was associated with a higher risk of mortality following hip fracture. Secondly, smoking impairs redox balance, increases the expression of pro-inflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-6, and interleukin-8, and impairs mucociliary clearance and pulmonary immunity, leading to severe infections31. This process can cause cytokine release, characterized by the overproduction of inflammatory mediators, which are associated with adverse outcomes in patients with hip fracture32. Additionally, cigarette smoking affects soft-tissue structures and peripheral blood flow, increases the risk of infection in operative wounds and soft-tissue flaps, and impairs bone-healing by decreasing osteoblast activity, collagen synthesis, and angiogenesis33. These complications may prolong hospital stay and increase mortality.The increased risk of hip-fracture mortality in smoking patients can be explained by several mechanisms. Firstly, smoking increases the incidence of various diseases, including malignancy, cardiovascular and pulmonary disorders34. Our study showed ever-active smokers had significantly higher death risk than never smokers in elderly fracture patients. More comorbidities induced by smoking in elderly correlate with higher rates of worse prognosis and mortality, which is consistent with numerous studies28. Chatterton et al.28 reported older age and comorbidity are significantly associated with early in-hospital mortality of hip fracture, with respiratory infections and cardiovascular disease the predominant causes of death. Von et al.26 found age at hip fracture was the most important predictor of long-term mortality, where the very elderly only survive for a very short time, with cardiovascular disease as the most common cause of death.Hip fracture is very common in elderly patients, especially those aged ≥60The analyses revealed that current smoking increased the risk of mortality after hip fracture compared with never smoking, with no significant difference between current smokers and former smokers, suggesting that the influence of smoking on hip-fracture mortality would persist even after smoking cessation. It also illustrated that never smoking may be the effective solution to reduce the mortality of hip fracture in comparison to smoking cessation.17. However, few studies assessed the association between smoking and short-term and long-term mortality in hip fracture. Our analysis showed that ever-active smoking was significantly linked to a risk of mortality in hip-fracture patients in follow-up periods of ≤1 year, 3 years and 5 years, indicating the effect of smoking on mortality is profound and lasting with the extension of follow-up period.Previous studies have shown hip fracture was a significant risk factor contributing the most to long-term as well as short-term excess mortalityThis study has some limitations. First, despite that low heterogeneity was found across publications, we cannot rule out the possibility that other inadequately measured factors may bias the associations. Second, although we conducted a comprehensive and systematic literature search with well-defined inclusion and exclusion criteria, most studies did not define smoking status or provided enough data on smoking history (the smoking status questionnaire administered as part of routine care did not assess the duration and amount of smoking by former smokers or smoking cessation during follow-up). Third, although the analysis indicated different outcomes between smoking and hip-fracture mortality in White and Asian participants, more studies with larger sample sizes are needed to confirm the results.This is the first systematic review and meta-analysis on the association between cigarette smoking and mortality in patients with hip fracture. Judging from the present results, the mortality risk was higher in ever-active smokers, especially in elderly patients aged ≥60 years, current smokers and White participants. With the extension of follow-up period, the effect of smoking on mortality is profound and lasting. The high mortality rate in these patients should serve as an incentive, for the patients and also for at-risk populations, to quit smoking. In addition, more data on smoking status should be analyzed to accurately estimate the effects of smoking on hip-fracture mortality.Click here for additional data file.


Which total hip arthroplasty approach is associated with the best efficacy and acceptability?In this systematic review and meta-analysis of 63 randomized clinical trials of surgical approaches for total hip arthroplasty with 4859 participants, all surgical approaches except the direct lateral approach were associated with greater improvements of hip score when compared with the posterior approach. The safety of different approaches did not show significant differences.These findings may support improved clinical decision-making among health care professionals and patients and also provide information for policy makers. This systematic review and meta-analysis evaluates the efficacy and safety associated with different surgical approaches for total hip arthroplasty. Each approach for primary total hip arthroplasty (THA) has a long learning curve, so a surgeon’s choice to change their preferred approach needs to be guided by clear justifications. However, current evidence does not suggest that any of the THA approaches are more beneficial than others, and the choice of approach is mainly based on the knowledge and experience of the surgeon and individual patient characteristics.To assess the efficacy and safety associated with different surgical approaches for THA.A comprehensive search of PubMed, EMBASE, and Cochrane databases from inception to March 26, 2022; reference lists of eligible trials; and related reviews.Randomized clinical trials (RCTs) comparing different surgical approaches, including the 2-incision approach, direct anterior approach (DAA), direct lateral approach (DLA), minimally invasive direct lateral approach (MIS-DLA), minimally invasive anterolateral approach (MIS-ALA), posterior approach (PA), minimally invasive posterior approach (MIS-PA), and supercapsular percutaneously assisted total hip arthroplasty (SuperPath), for primary THA.Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, 2 reviewers independently extracted data on study participants, interventions, and outcomes as well as assessed the risk of bias using the Cochrane risk of bias tool and the certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation framework. A frequentist framework was used to inform a series of random-effects network meta-analyses.The outcomes were hip score , pain score , hospitalization time, operation time, quality of life score, blood loss, cup abduction angle, and cup anteversion angle.Of 2130 retrieved studies, 63 RCTs including 4859 participants  were eligible for analysis. Eight surgical approaches were evaluated. For hip score, DAA , MIS-ALA , MIS-DLA , MIS-PA , PA , and SuperPath  were associated with greater improvement in hip score compared with DLA. DLA was associated with lower decrease in pain score than SuperPath  and MIS-DLA . PA was associated with shorter operation times compared with 2-incision , DAA , DLA , MIS-ALA , and SuperPath . The incidence of 6 types of complications did not differ significantly between the approaches.In this study, moderate to high certainty evidence indicated that compared with PA, all surgical approaches except DLA were associated with similar improvements of hip score but longer operation time. DLA was associated with smaller improvement of hip score. The safety of the different approaches did not show significant differences. These findings will help health professionals and patients with better clinical decision-making and also provide references for policy makers. The optimal surgical approach for THA remains inconclusive. According to the National Institute for Health and Care Excellence 2020 guideline, current evidence does not suggest that any of the THA approaches are more beneficial than others, and the choice of approach is mainly based on the knowledge and experience of the surgeon and individual patient characteristics.15 Each approach has a long learning curve, so a surgeon’s choice to change their preferred approach needs to be guided by clear justifications.19The choice of operative approach can affect the efficacy and safety of THA.22 The vague definitions of approaches in some studies can lead to classification errors and hence inaccurate comparisons. In addition, existing meta-analyses have not assessed the certainty or quality of evidence.23 Addressing these gaps, we performed a network meta-analysis of randomized clinical trials (RCTs) to compare existing THA approaches of efficacy and safety through comprehensive evidence synthesis of both direct and indirect comparisons. Patients who underwent primary THA for any indication were included in this analysis, and the outcome time point was set as the follow-up end point.Most existing research compares only 2 approaches, and there is a lack of evidence for head-to-head comparisons among all existing approaches for THA. Limited reviews have used rigorous meta-analytical techniques to obtain quantitative estimates of the outcomes for different approaches.CRD42020221715) and reported our study following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and PRISMA-2020 guidelines and the extension statement for network meta-analysis (PRISMA-NMA).25A multidisciplinary panel consisting of orthopedic surgeons, rehabilitation physicians, an epidemiologist, a systems evaluation expert, and a statistician provided input into the study protocol. We registered our protocol on the PROSPERO  were searched to identify studies on surgical approaches in THA. We updated our search on March 26, 2022, to include recent eligible trials. In addition, ClinicalTrials.gov was searched to identify additional studies and unpublished data. The detailed search strategy is shown in eAppendix 1 in The inclusion criteria were (1) studies that included patients undergoing primary THA surgery for any indication; (2) studies that compared at least 2 surgical approaches for THA, without restricting the control group setting; (3) studies presenting any relevant outcome measures  working independently. Reviewers addressed discrepancies through adjudication by a third reviewer (L.Y.). If a study reported outcomes at several time points, the longest follow-up was used for analysis.We collected information regarding patient characteristics , surgery details , and all reported outcome measures . The definitions of these 8 outcomes and 24 other outcomes are shown in eTable 1 in 26: (1) hip score to Harris hip score (0-100), where higher scores represent better outcomes, and (2) pain score to the 100-mm visual analogue scale, where higher scores represent worse outcomes. Since the different scales of QOL used across included studies could not be converted to a single scale, the Hedges method was used to calculate the standardized mean difference (SMD) for the QOL. The mean difference (MD) was calculated for all other indicators except QOL.We converted hip score and pain score to a common scale on a domain-by-domain basis for better clinical interpretabilityCochrane Handbook to calculate MD and SD for change.27 When SDs were missing, we estimated them from SEs, P values, confidence intervals, or graphs. If none of these methods was feasible, we derived SDs from other studies included in our network meta-analysis using a validated imputation technique  . We used the networkplot command of Stata version 16.0 (StataCorp) to draw the network plots.34 The detailed methods of multiple sensitivity analyses are presented in eAppendix 2B in 35 The change from protocol is displayed in eAppendix 2D in We compared distributions of characteristics across study groups, organized by approaches, to assess the transitivity assumption of indirect comparisons. Local inconsistency of direct and indirect results was assessed with the node-splitting method for all comparison loops, and indirect results were derived from direct and network results by the back-calculation method.23 The Cochrane Collaboration Risk of Bias 1 (ROB-1) tool36 was used independently by 2 reviewers (D.L. and another researcher) to evaluate the risk of bias of included studies  framework, which classifies evidence as high, moderate, low, or very low certainty. The starting point for certainty in direct estimates for RCTs is high, but it could be rated down based on limitations due to risk of bias, imprecision, inconsistency (heterogeneity), indirectness, and publication bias.92 were eligible for inclusion  showed relevant information, with surgeons in 7 studies92 (11.1%) in the learning phase and surgeons in the remaining 28 studies93 (38.1%) experienced  age of 64.0 (60.3-66.5) years, median (IQR) body mass index  of 27.00 (25.58-28.27), median (IQR) percentage male of 46.74% (38.64%-54.74%) and median (IQR) follow-up time of 1.0 (0.5-2.0) years  with 3882 participants (80%) reported on hip score change from baseline to end point  with 1936 participants (40%) reported on pain score change from baseline to endpoint  with 2702 participants (56%) reported on hospitalization time  with 3437 participants (71%) reported on operation time  with 1904 participants (31%) reported on QOL score change from baseline to end point  with 2702 participants (56%) reported on blood loss  with 2364 participants (49%) reported on cup abduction angle, and 18 studies93 (26%) with 1392 participants (29%) reported on cup anteversion angle  and that all procedures are performed by the same experienced surgeon to improve the comparability of data. In addition, we recommend using the same incision appearance to achieve double-blinding. Finally, we advise larger sample sizes and longer follow-up periods to obtain more reliable long-term results.We also note several limitations in our study. First, publication bias was detected in some of the outcomes, the consequences of which could be reduced by adequate retrieval. Second, the heterogeneity of different implants and surgeon expertise across the included studies was not accounted for in our analysis. Third, our analysis did not include the cost of each approach. Fourth, some of the approaches lacked evidence for direct comparisons, which may have affected our findings. The findings of our study should be interpreted with consideration given to these limitations.This systematic review and network meta-analysis provides important information for the choice of surgical approach for primary THA. Moderate to high certainty evidence indicated that compared with PA, all surgical approaches except DLA were associated with similar improvements in hip score but longer operation time. DLA was associated with lower improvement in hip score and higher blood loss. These findings will aid clinicians in balancing the risks and benefits of available approaches for primary THA and provide key evidence for producing recommendations for clinical practice.


Clinical practice guidelines discourage routine preoperative screening tests for patients undergoing low-risk procedures. This study sought to determine the frequency and costs of potentially low-value preoperative screening tests in Veterans Health Administration (VA) patients undergoing low-risk procedures.Using the VA Corporate Data Warehouse, we identified Operative Stress Score class 1 procedures (“very minor”) performed without general anesthesia in VA during fiscal year 2019 and calculated the overall national and facility-level rates and costs of nine common tests received in the 30 preoperative days. Patient factors associated with receiving at least one screening test, and the number of tests received, were examined.Eighty-six thousand three hundred twenty-seven of 178,775 low-risk procedures (49.3%) were preceded by 321,917 potentially low-value screening tests representing $11,505,170 using Medicare average costs. Complete blood count was the most common (33.2% of procedures), followed by basic metabolic profile (32.0%), urinalysis (26.3%), electrocardiography (18.9%), and pulmonary function test (12.4%). Older age, female sex, Black race, and having more comorbidities were associated with higher odds of low-value testing. Transthoracic echocardiogram occurred prior to only 4.5% of the procedures but accounted for 47.8% of the total costs . In 129 VA facilities, the facility-level proportion of procedures preceded by at least one test ranged from 0 to 81.2% and facility-level costs ranged from $0 to $388,476.Routine preoperative screening tests for very low-risk procedures are common and costly in some VA facilities. These results highlight a potential target to improve quality and value by reducing unnecessary care. Measures of low-value perioperative care could be integrated into VA’s extensive quality monitoring and improvement infrastructure.The online version contains supplementary material available at 10.1186/s13741-022-00265-0. Screening tests prior to surgical and other medical procedures are justified if they produce actionable data that might alter clinical management or patient outcomes. However, for patients undergoing low-risk procedures, preoperative screening tests often do not change clinical management, sometimes lead to unnecessary follow-up testing and interventions, and can cause delays in receiving surgery  determine the overall and facility-level rates of receiving any of nine common low-value preoperative tests in the 30 days prior to any Operative Stress Score (OSS) I (“very minor”) procedures performed without general anesthesia in the VA in fiscal year 2019; (2) examine the patient factors that are associated with receiving at least one low-value test and the number of tests received; and (3) estimate the overall and facility-level costs of low-value preoperative testing. Knowing more about the overall burden of potentially unnecessary preoperative testing, as well as associated patient factors, might inform and motivate the development of interventions to reduce low-value care, especially in locations where the burden is highest.All data were derived from the VA Corporate Data Warehouse (CDW), a nationwide database of all VA healthcare records. The cohort consisted of VA patients undergoing low-risk procedures in fiscal year 2019. More than one procedure per patient was included if the surgery dates were separated by at least 30 days.The expanded Operative Stress Score (OSS) was developed to classify 5753 Category I Current Procedural Terminology (CPT) codes into five categories of physiologic stress ; basic metabolic panel (BMP); coagulation tests; urinalysis; electrocardiography (EKG); pulmonary function tests (PFT); trans-thoracic echocardiograms (TTE); cardiac stress tests, and chest x-rays. Tests were excluded if they occurred within 30 days prior to an OSS 2–5 procedure that may have justified it.Patient characteristics included age at time of the procedure, gender, race/ethnicity, marital status, service connection status , and 30 diagnoses included in the Elixhauser Comorbidity Index  reimbursement Fee Schedule for physician fees, facility fees, and the CMS clinical laboratory fee schedule for 2019 were used to assign a cost to each preoperative screening test.p values were produced for all regression model coefficients.Overall and facility-level rates of OSS 1 procedures that were preceded by at least one low-value test were calculated. Rates of OSS 1 procedures preceded by each of the nine tests were also calculated. Mixed-effects logistic regression was used to examine associations between patient characteristics  and receipt of at least one low-value test, with random intercepts for the VA facility where the procedure was performed  involved at least one screening test in the 30 preoperative days. Among the 44,545 OSS I procedures that were excluded involving general anesthesia, 82.5% were preceded by at least one screening test. Characteristics of the cohort, stratified by receipt of any preoperative screening test, are presented in Table As presented in Table In 129 VA facilities, the facility-level proportion of low-risk procedures preceded by at least one test ranged from 0 to 81.2% Fig. , older aHigh-value, patient-centered health care includes selectively ordering preoperative tests that may inform clinical management or improve patient outcomes. Tests unlikely to meet these criteria may cause avoidable harm, inconvenience, and waste of resources that could be used for higher-value services. For years, government healthcare agencies and professional organizations have been recommending the avoidance of routine preoperative testing for low-risk procedures  or tests that are unrelated to the OSS1 procedures. If the distribution of testing was uniformly modest , the case for investments in quality improvement might be easier to dismiss. However, we can see in Figs. Beyond describing the magnitude and distribution of opportunities for quality improvement, another purpose of this study was to identify the patient characteristics associated with preoperative testing. We found older age, being female, not married, black, and having comorbidities were all associated with higher odds of testing. The large ICC in the model predicting receipt of at least one test (0.189) suggests that much of the variance in preoperative testing is at the facility-level. In other words, the likelihood of getting tested is as much a function of where you are treated as your specific medical profile.Although excluded from our primary analyses, general anesthesia was received for 16.5% of OSS1 procedures in FY19, of which 82.2% underwent preoperative testing. Anesthetic risk, not just procedural risk, needs to be factored into the decision to order preoperative tests. We previously found that much of the variance in using general anesthesia for a low-risk procedure  is driven by clinician or facility factors rather than patient characteristics or preferences  can be designed and implemented to improve the quality of care by providing less of it.Additional file 1: Supplemental Table 1. Patient Characteristics Associated with Number of Preoperative Screening Tests Received.


During an infectious disease progression, it is crucial to understand the cellular heterogeneity underlying the differential immune response landscape that will augment the precise information of the disease severity modulators, leading to differential clinical outcome. Patients with COVID-19 display a complex yet regulated immune profile with a heterogeneous array of clinical manifestation that delineates disease severity sub-phenotypes and worst clinical outcomes. Therefore, it is necessary to elucidate/understand/enumerate the role of cellular heterogeneity during COVID-19 disease to understand the underlying immunological mechanisms regulating the disease severity. This article aims to comprehend the current findings regarding dysregulation and impairment of immune response in COVID-19 disease severity sub-phenotypes and relate them to a wide array of heterogeneous populations of immune cells. On the basis of the findings, it suggests a possible functional correlation between cellular heterogeneity and the COVID-19 disease severity. It highlights the plausible modulators of age, gender, comorbidities, and hosts’ genetics that may be considered relevant in regulating the host response and subsequently the COVID-19 disease severity. Finally, it aims to highlight challenges in COVID-19 disease that can be achieved by the application of single-cell genomics, which may aid in delineating the heterogeneity with more granular understanding. This will augment our future pandemic preparedness with possibility to identify the subset of patients with increased diseased severity. Therefore, understanding the diversity of disease severity and clinical outcomes, requires uncovering the functional diversity of cells. The outcome modulation by this cellular heterogeneity can imply distinct functionality necessary during a diseased state for survival conditions  platforms have been critical toward this as they generate huge amounts of data . With buogeneity . During ogeneity .This article aims at highlighting the role of cellular heterogeneity across infectious disease, particularly the COVID-19. This includes the different levels of immune response defining the host’s response with disease phenotype and correlation of the heterogeneous population of immune cells with COVID-19 disease severity and clinical outcome. It provides a compendium of insights on the possible clinical outcome of a disease from the cellular heterogeneity perspective, based on the clinical phenotypes.While understanding the infectious diseases, COVID-19 pandemic has surpassed the previous known global infectivity and is one of the major infectious diseases of the era. The single-stranded RNA virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causes COVID-19, which is a heterogeneous disease with a variable range of severity symptoms. The clinical presentation of COVID-19 varies from predominantly asymptomatic and mild-to-moderate episodes to more severe and critical, where 10%–20% of patients develop acute respiratory distress syndrome (ARDS) and pneumonia . AlthougThe COVID-19 disease severity sub-phenotype is categorized by World Health Organization (WHO) into asymptomatic, mild, moderate, severe, and critical, where there is a clear distinction based on clinical symptoms that they exhibit Table 1 Although there is an increasing amount of knowledge on the host immune response to SARS-CoV-2 infection and the pathogenesis of COVID-19, it is still not apparent why some patients progress to severe illness, whereas others present mild symptoms or are asymptomatic. Therefore, it is crucial to define the immunological and inflammatory components of SARS-CoV-2 infection in great detail. The rationale behind different clinical outcomes based on immune profiles of patients infected with similar viral strain could be possibly due to cellular heterogeneity Figure 1The role of cellular heterogeneity is essential to understand the mechanism by which a complex network of billions of specialized immune cells functions in harmony and produces a coordinated host response against COVID-19. During a viral infection, there are two different layers of the immune system, i.e., innate and adaptive, which functions one after the other to restrict the entry of virus or prevent it from bypassing the host’s immune system , 21. TheInnate immune cells carry pathogen recognition receptors (PRRs) on their surface that, upon viral entry, trigger inflammatory signals through recognition and binding of harmful viral particles that behave as pathogen-associated molecular patterns. On the other hand, intrinsic compounds, such as heat shock proteins, are released from viral-infected or damaged cells that act as damage-associated molecular patterns and activate innate immune and inflammatory responses by interacting with PRRs. Nucleotide-binding oligomerization domain, Toll-like receptors (TLRs), C-type lectin receptors, a retinoic acid–inducible gene I–like receptors (RLRs), and absent in melanoma 2–like receptors are the most prevalent PRRs in the host . Among tThe innate immune cells are the primary target for successful SARS-CoV-2 infection . MacrophbrightCD16neg NK-cell subset majorly produces cytokines, and the CD56dimCD16pos NK-cell subset is characterized by strong cytotoxicity and high expression of inhibitory receptors such as killer cell immunoglobulin-like receptors.  composition between patients with severe and mild COVID-19. This was supported by an increased CD14+ monocyte population and decreased CD16+ non-classical monocyte, CD14+CD16+ monocytes, and DC2 in severe patients compared with mild patients and healthy individuals . Whereasceptors. . Among tseverity . In contseverity , which iseverity . Zheng eseverity . It can In contrast to the innate mechanism of host defense, the adaptive immune system exhibits specificity for its target antigen. Humoral and cellular immunity forms the adaptive or acquired immune response, where B and T lymphocytes, respectively, provide antigen-specific responses . The abiSu et al. reported that, during COVID-19, several B-cell subsets, including naive B cells and antibody secreting cells, were elevated in severe patients, whereas memory B cells were increased in mild patients, suggesting a heterogeneous B-cell population across COVID-19 disease sub-phenotypes . Patientvia effector CD8+ T cells provides evidence of elevated cytotoxicity induced in severe patients  is present on the 3p21.31 locus and encodes the sodium–imino acid (proline) transporter 1 (SIT1), which is known to interact with the ACE2 receptor  are one of the major players involved in antigen presentation to the lymphocytes, further activating the host immune response  of TMPRSS2 polymorphisms may serve as predictive model for COVID-19 severity  is of paramount importance in providing relevant information at single-cell resolution with the highest granularity that can aid in a comprehensive understanding of cellular immune response during COVID-19. Rather than using composites or averages from multiple cells, single-cell approaches offer a high-resolution perspective into these subsets and individual cells. Furthermore, multi-omics profiling of concurrent readouts from the same cell, including gene expression, cell surface proteins, and receptor sequences, enables more accurate and reliable characterization of these heterogeneous cell populations. From evidence within patients with COVID-19, where T-cell population is immensely variable, the single-cell profiling of T-cell subsets can be performed on a clinical cohort to understand insights of T-cell–mediated response and T-cell receptor repertoire dynamics. Detailed characterization of both CD4+ T cells and CD8+ memory T cells using single-cell omics can be helpful in patient categorization and plausible future protection. Understanding from the perspective of genes involved in defining the particular cell states during severe COVID-19 can also help us to elucidate the role of cellular heterogeneity in disease severity. Single-cell omics approach will help address the unresolved query concerning cellular heterogeneity that may assist us in preparing for the future as the SARS-CoV-2 is continuously evolving with acquired immune escape capabilities.Understanding cellular heterogeneity in COVID-19 can be a cumbersome task as it comes with many challenges Figure 4Author contribution KK has read the relevant literature, synthesized the findings, wrote the manuscript and made the figures. RP planned the study, wrote the manuscript, coordinated the manuscript outline, figures, conclusions and future challenges/opportunities. Both the authors contributed to the article, have read and approved the final submission.The study was supported by Bill and Melinda Gates Foundation (BMGF), INV-033578, Foundation for Innovative New Diagnostics (FIND), project code – GAP-0249, and AIDS Healthcare Foundation (AHF), project code CLP0043.KK acknowledges the fellowship from CSIR toward her salary support.The authors declare that the article was written 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.


This cross-sectional study assesses whether the increase in adult and pediatric and neonatal mechanical ventilators in US hospitals in response to the COVID-19 pandemic varied across hospital structural features, region, and safety-net status. Therefore, we performed an updated assessment of current ventilators in use at US hospitals to aid with current and future pandemic preparedness and to determine whether any change was correlated with COVID-19 burden.Despite the unprecedented demand for mechanical ventilators in the US during the COVID-19 pandemic, the last survey of US hospitals occurred in 2010 and estimated approximately 62 000 full-featured ventilators.3 We assessed whether the increase in adult and pediatric and neonatal mechanical ventilators in US hospitals varied across hospital structural features, region, and safety-net status using a multivariable regression model weighted by likelihood of survey response to create national-level estimates. We then created a map of current adult mechanical ventilators per 100 000 residents using the state-level population estimates from the 2020 US Census.4 A state-level analysis used Pearson statistics to assess the correlation between increase in ventilators per capita and COVID-19 intensive care unit (ICU) admissions per capita. Analyses were performed with SAS, version 9.4M7 (SAS Institute Inc). Two-sided P < .05 indicated statistical significance. This study was deemed exempt from review by the institutional review board of the Harvard T. H. Chan School of Public Health owing to the use of deidentified hospital-level data. We followed the STROBE reporting guideline.In this cross-sectional study, we used new survey data from the 2020 American Hospital Association (AHA) Annual Survey to estimate the increase in mechanical ventilator supply. The ventilator questions were developed in response to the COVID-19 pandemic and were fielded for the first time in 2020. Data from the AHA were merged with US Census data and COVID-19 burden data from the Department of Health and Human Services for 2020 to correspond with the AHA survey year.P < .001), major teaching hospitals , and not for profit . Of hospitals providing pediatric care, 1103 of 1397 responded . The multivariate adjusted relative increase in adult mechanical ventilators during the public health emergency in 2020 was 31.5%  (P = .03).In total, 2712 of 4609 US adult acute care hospitals responded to the survey . Responding hospitals were more likely to be large  . The sta < .001) . The incr = 0.13; P = .37).South Carolina, Alaska, Nevada, Idaho, and Mississippi had the lowest per capita supply of adult mechanical ventilators, whereas New York, Louisiana, Arkansas, North Dakota, and Washington, DC, had the highest per capita supply . The sta5 The increase in ventilators that were deployed in hospitals was not correlated with the state’s COVID-19 ICU burden, but this finding may not account for more dynamic shifts in ventilator stock across hospitals during waves of the pandemic. For both the current COVID-19 pandemic as well as future pandemic preparedness, these findings may help guide policy makers in deploying ventilators to states with the most urgent need of ventilators.This cross-sectional study found a substantial increase in adult and pediatric mechanical ventilators reported by acute care hospitals in 2020 compared with 2019. Study limitations include possible response bias. The AHA Annual Survey did not differentiate between ventilator functionality, changes in numbers of anesthesia ventilators, or transport, backup, or rental ventilators, nor did it account for temporary ventilator allocation coordinated through state public health departments or the Dynamic Ventilator Reserve.


Potential aerosols containing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral particles can be generated during dental treatment. Hence, patient triage is essential to prevent the spread of SARS-CoV-2 in dental clinical settings. The present study described the use of rapid antigen tests for SARS-CoV-2 screening prior to dental treatment in an academic dental clinical setting in Thailand during the pandemic. The opinions of dental personnel toward the use of rapid antigen test screening prior to dental treatment were also assessed. From August 25 to October 3, 2021, dental patients who were expected to receive aerosols generating dental procedures were requested to screen for SARS-CoV-2 using a rapid antigen test before their treatment. A total of 7,618 cases completed the screening process. The average was 212 cases per day. Only five patients (0.07%) were positive for SARS-CoV-2 in the rapid antigen screening tests. All positive cases exhibited mild symptoms. For the questionnaire study, experienced dental personnel frequently and consistently agreed with the use of the rapid antigen test for SARS-CoV-2 screening, which made them feel safer during their patient treatment. However, implementing rapid antigen tests for SARS-CoV-2 may increase the total time spent on a dental appointment. In conclusion, a rapid antigen test could detect the infected individual prior to dental treatment. However, the specificity of rapid antigen tests for SARS-CoV-2 must be taken into account for consideration as a screening process before dental treatment. The enhanced infection control protocols in dental treatment must be consistently implemented. In December 2019, a report identified a cluster of pneumonia cases in China. These infections were later unveiled upon the intriguing discovery of a new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) . In addiBecause SARS-CoV-2 could be detected in the saliva , the sprPoint-of-care SARS-CoV-2 testing was recommended prior to dental treatment in those cases where the risk is high enough to increase the complexity of dental treatment . Point-oAnother approach for SARS-CoV-2 detection is antigen testing. A rapid antigen test is proposed as a simple screening tool for identifying asymptomatic cases, as the agreement between the rapid antigen test and RT-PCR was high . It has The present study described using a rapid antigen test for SARS-CoV-2 prior to dental treatment in a Thai Dental Hospital. Dental personnel were surveyed to evaluate the benefits and limitations of using the rapid antigen screening test prior to dental treatment.This study was approved by the Human Research Ethical Committee of the Faculty of Dentistry at Chulalongkorn University in the province of Bangkok in Thailand (certificate no. 077/2021). The retrospective study was performed in accordance with the ethical standards of the institution. Inform consent was obtained from the participants in the questionnaire study.+ , Standard Q COVID-19 Ag Test , and Humasis COVID-19 test . All kits were approved by the Thai Food and Drug Administration and available in the market at the time of the fourth wave of the pandemic in Thailand (July–September 2021). At the Center for SARS-CoV-2 Rapid Antigen Test, the biosafety unit installed on a modified truck trailer was donated by the King Mongkut Chaokhun Thahan Hospital Foundation and King Mongkut's Institute of Technology Ladkrabang. The biosafety unit was equipped with a standard controlled air ventilation system featuring a positive air pressure environment with an integrated HEPA filter. Hospital records were used to retrieve each subject's clinical information (age and gender). For those cases that had a positive antigen test, patients were informed to confirm with RT-PCR methods.From August 25 to October 3, 2021, a retrospective study was performed on dental patients who received the rapid antigen test for SARS-CoV-2 screening prior to their procedures at the dental clinics located in the Faculty's Hospital. Only patients who required aerosol-generating dental procedures were requested to complete rapid antigen screening, which was carried out at the Center for SARS-CoV-2 Rapid Antigen Test, located in the Faculty of Dentistry. Referring patients for SARS-CoV-2 screening also depends on the judgment of dentists. Patients were required to come 1 h before their scheduled dental appointments to take their rapid antigen test, and their screening results were valid for 72 h. A nasopharyngeal swab method was employed to collect samples by trained medical personnel. Three types of rapid antigen test kits were utilized, namely, Biosynex Autotest Antigénique COVID-19 Agvia online chat rooms with total members of 1,443. The data were collected from November 11 to December 1, 2021, using the convenience sampling method and approach design. Data were exported into the Excel format and subsequently analyzed.A self-administered questionnaire was designed by the authors and created online using a Google form format. The consent statement was displayed on the first page of the questionnaire. The first section of the same questionnaire collected sociodemographic data, including working position in the faculty, gender, and age. The second section was composed of five questions , and eacA descriptive statistical analysis was first performed. Graphical illustrations were formulated using Prism 9 for MacOS version 9.2.0 . The descriptive analyses were performed to describe the characteristics of the population in the study. Statistical analysis of questionnaire responses was performed using Wilcoxon's sum rank. A 5% alpha level was set as the statistical cutoff.During the rapid antigen screening period , the overall number of new daily cases of SARS-CoV-2 and deaths in the province of Bangkok (Thailand), where the faculty is located, gradually decreased. On the first screening day, new confirmed cases were 4,181, and the daily death toll was 99, while on the last screening day, there were 1,221 new cases and 20 deaths.A total of 7,618 dental patients visiting the Faculty of Dentistry Clinics at the Chulalongkorn University campus required a rapid antigen screening test for SARS-CoV-2 prior to their dental appointments. The average number of dental patients receiving the rapid antigen test was 212 per day. Among these dental patients, 38.7% were males. Further demographic characteristics are described in The Standard Q COVID-19 Ag Test kits were employed in 93.1%  of dental patients. The Biosynex and Humasis COVID-19 antigen test kits were used in 6.0% (454 cases) and 0.9% (71 cases) cases, respectively. The usage amount of each antigen test kit was linked to the available supply. For Thai nationals, the cost of the rapid antigen test screening for SARS-CoV-2 was paid through the Universal Health Coverage, National Health Security Office (NHSO). Only 56 dental patients (0.73%) paid out of pocket for the screening tests as they did not possess Thai nationality.Of all 7,618 dental patients, 99.93% tested negative for the COVID-19 rapid antigen test. Five dental patients (0.07%) had a positive result: three females and two males, aged 28–65 years old. Dental patients with positive antigen test results were referred to further confirm such findings with RT-PCR and enrolled into the COVID-19 treatment registry for proper treatment. All positive dental patients were detected with the Standard Q COVID-19 antigen test kits. All positive dental patients exhibited at least one hallmark COVID-19 symptom, such as sore throat, coughing, and stuffy nose.A total of 101 responses were obtained. The responses were from undergraduate students (32.7%), dentists/postgraduate students (31.7%), and other faculty personnel (35.6%) . Most ofp < 0.05).A summary of responses from self-administered questionnaire outcomes is given in via phone or online interview as all patients must be absent of any symptoms prior to the reservation of dental treatment. A point-of-care screening could benefit COVID-19 symptoms triage prior to dental treatment if a strict and calibrated patient screening protocol is performed by phone and online tools. This could potentially detect all these positive cases before their visits.The present study reported that only 0.07% of screened subjects using the rapid antigen test prior to their dental treatment had a positive result. After discussion with dental patients who had positive antigen tests, it was found that all of them exhibited at least one hallmark COVID-19 symptom such as sore throat, cough, and stuffy nose; however, all these COVID-19 symptoms were very mild. Phone or online screening for potential COVID-19 signs and symptoms was employed before the dental appointment. The dental personnel in charge of subject screening missed detecting these mild COVID-19 symptoms In the legal context of Thailand, screening for SARS-CoV-2 is not a standard mandatory requirement for dental patients prior to dental treatment. At the Chulalongkorn University Faculty of Dentistry Dental Clinics, RT-PCR screening for SARS-CoV-2 is required for those patients who need treatment in the operation room. Because the cost of the rapid antigen test is substantially lower than that of the standard RT-PCR, the antigen test was implemented to identify asymptomatic COVID-19 patients. Regardless, the cost of the rapid antigen test was not a relevant financial burden for subjects participating in this study as it was covered by the Universal Health Coverage for all Thai nationals. However, implementing point-of-care screening in other settings, particularly for-profit like private dental practices, may lead to an increase in manpower costs, which may be transferred to the final treatment expense bill of dental patients seen in those settings.The detection rate of COVID-19-positive dental patients was much lower than the incidence of daily COVID-19 cases seen in Bangkok during the same period. The explanation might be that dental patients are aware of the close contact between the dentist and their oral cavity and the high risk of exposure to potentially contaminated saliva with SARS-CoV-2 viral particles. Therefore, generally speaking, dental patients were cautious about their potential exposure to SARS-CoV-2. Most importantly, in general, those patients who were comfortable seeking dental treatment during the fourth wave of the pandemic in Thailand had received a complete vaccination scheme. However, to make a dental appointment, vaccination was not mandatory for participants/patients enrolled in this study. Thus, the population sample of those who came to our hospital might not be the same as the general population regarding their vaccination status.It has been reported that sample collection can influence the performance of the rapid antigen test. The rapid antigen test exhibited higher sensitivity for SARS-CoV-2 detection when used with nasopharyngeal swabs than saliva and throat swab samples , 17. HowThe rapid antigen test can be used in population-based screening to identify asymptomatic individuals and control the spread of SARS-CoV-2 viral infection . HoweverRecently, it has been reported that rapid antigen tests can be helpful for the initial screening of patients in emergency units . HoweverDuring the data collection period, the dental personnel were not required for rapid antigen test screening prior to duty due to the limited supply available. In the dental treatment procedure, all dental personnel were strictly required to wear personal protective equipment, including N95 masks. Hence, the risk for transmission was relatively low. However, dental personnel could request rapid antigen test screening if they were suspected of COVID19-related symptoms or in close contact with the SARS-CoV-2 positive cases.The overall perception of faculty personnel  regarding the use of the rapid antigen test for SARS-CoV-2 screening exhibited a striking agreement upon its use on both patients and dental personnel prior to dental treatment sessions. The faculty personnel considered that this screening test could make them feel safer during dental appointments. The majority of undergraduate students strongly disagree with the statement that the rapid antigen test for SARS-CoV-2 screening does not time-consuming and is less complex. However, the rapid antigen test screening was performed by trained medical personnel, and patients were asked to come 1 h prior to their dental appointment. The registration steps for hospital records and the reimbursement from the Universal Health Coverage caused an accumulation of patients at the Center for SARS-Cov-2 Rapid Antigen Test, leading to the delay in the early morning (8.00 am–10.00 am) and afternoon (12.30 pm–2.00 pm) sessions. Most undergraduate students are concerned that such screening adds additional steps and more time constraints during dental appointments since these students are heavily involved and committed to patient dental care to be able to graduate successfully.The present study did not collect the vaccination status and/or antibody levels against SARS-CoV-2 of those patients who had undergone antigen test screening. This information could help to understand the observation of a low percentage of SARS-CoV-2 antigen test positive prior to dental treatment during the period of screening in this project. In addition, the current observation employed three types of antigen test kits. Although all the kits passed the standard and were certified by the Thai Food and Drug Administration, they might exhibit a slight difference in specificity and sensitivity, and this point should also be considered when interpreting the results. In addition, for the self-administered questionnaire, the survey was sent to 1,433 people, but only 101 responses were obtained; hence, the interpretation of the outcomes may be performed with the caution noted that this sampling may not directly represent the targeted population.The present study reported low incidence rates of SARS-CoV-2 with three rapid antigen screening tests prior to dental treatment. All positive dental patients had mild symptoms related to COVID-19. Hence, a standard calibrated phone/online patient screening procedure prior to dental appointments is deemed essential to exclude potentially infected individuals. The implementation of rapid antigen tests for SARS-CoV-2 as a point-of-care screening method should be carefully considered due to the additional costs for the national health care system and clinical settings. With vaccination coverage and decreasing severe symptom cases, the consideration for general screening prior to dental procedures might not be necessary. In addition, the low specificity of rapid antigen tests for SARS-CoV-2 must be considered for appropriate decision-making when aiming to achieve an effective screening process , 19, 20.