American University of Beirut Medical Center

BACKGROUND/AIMS: The diagnostic criteria for polycystic ovary syndrome (PCOS) in adolescence are controversial, primarily because the diagnostic pathological features used in adult women may be normal pubertal physiological events. Hence, international pediatric and adolescent specialty societies have defined criteria that have sufficient evidence to be used for the diagnosis of PCOS in adolescents. METHODS: The literature has been reviewed and evidence graded to address a series of questions regarding the diagnosis of PCOS during adolescence including the following: clinical and biochemical evidence of hyperandrogenism, criteria for oligo-anovulation and polycystic ovary morphology, diagnostic criteria to exclude other causes of hyperandrogenism and amenorrhea, role of insulin resistance, and intervention. RESULTS AND CONCLUSION: Features of PCOS overlap normal pubertal development. Hence, caution should be taken before diagnosing PCOS without longitudinal evaluation. However, treatment may be indicated even in the absence of a definitive diagnosis. While obesity, insulin resistance, and hyperinsulinemia are common findings in adolescents with hyperandrogenism, these features should not be used to diagnose PCOS among adolescent girls.

Metabolic syndrome (MetS) forms a cluster of metabolic dysregulations including insulin resistance, atherogenic dyslipidemia, central obesity, and hypertension. The pathogenesis of MetS encompasses multiple genetic and acquired entities that fall under the umbrella of insulin resistance and chronic low-grade inflammation. If left untreated, MetS is significantly associated with an increased risk of developing diabetes and cardiovascular diseases (CVDs). Given that CVDs constitute by far the leading cause of morbidity and mortality worldwide, it has become essential to investigate the role played by MetS in this context to reduce the heavy burden of the disease. As such, and while MetS relatively constitutes a novel clinical entity, the extent of research about the disease has been exponentially growing in the past few decades. However, many aspects of this clinical entity are still not completely understood, and many questions remain unanswered to date. In this review, we provide a historical background and highlight the epidemiology of MetS. We also discuss the current and latest knowledge about the histopathology and pathophysiology of the disease. Finally, we summarize the most recent updates about the management and the prevention of this clinical syndrome.

For the purpose of advanced breast cancer (ABC) guidelines, ABC comprises both inoperable locally advanced breast cancer (LABC) and metastatic breast cancer (MBC).1,2 Advanced/metastatic breast cancer remains a virtually incurable disease, with a median overall survival (OS) of about 3 years and a 5-year survival rate of around 25%,3,4 even in countries without major accessibility problems. Survival is strongly related to breast cancer subtype, with the major advances seen in human epidermal growth factor receptor 2 (HER2)-positive ABC.

Funding: Work on this article has been partially funded by the European Commission FP7 Program (grant agreement 258583) as part of the DECIDE project. Sole responsibility lies with the authors; the European Commission is not responsible for any use that may be made of the information contained therein.

CONTEXT: The International Association for Hospice and Palliative Care developed a consensus-based definition of palliative care (PC) that focuses on the relief of serious health-related suffering, a concept put forward by the Lancet Commission Global Access to Palliative Care and Pain Relief. OBJECTIVE: The main objective of this article is to present the research behind the new definition. METHODS: The three-phased consensus process involved health care workers from countries in all income levels. In Phase 1, 38 PC experts evaluated the components of the World Health Organization definition and suggested new/revised ones. In Phase 2, 412 International Association for Hospice and Palliative Care members in 88 countries expressed their level of agreement with the suggested components. In Phase 3, using results from Phase 2, the expert panel developed the definition. RESULTS: The consensus-based definition is as follows: Palliative care is the active holistic care of individuals across all ages with serious health-related suffering due to severe illness and especially of those near the end of life. It aims to improve the quality of life of patients, their families and their caregivers. The definition includes a number of bullet points with additional details as well as recommendations for governments to reduce barriers to PC. CONCLUSION: Participants had significantly different perceptions and interpretations of PC. The greatest challenge faced by the core group was trying to find a middle ground between those who think that PC is the relief of all suffering and those who believe that PC describes the care of those with a very limited remaining life span.

Advanced Breast Cancer (ABC) comprises both locally advanced breast cancer (LABC) and metastatic breast cancer (MBC) [1]. Although treatable, MBC remains virtually an incurable disease with a median overall survival (OS) of ∼3years and a 5-year survival of only ∼25% [2, 3]. The MBC Decade Report [2] shows that progress has been slow in terms of improved outcomes, quality of life (QoL), awareness and information regarding ABC. More recently, some studies seem to indicate an improvement in OS, mostly due to advances in human epidermal growth factor receptor 2 (HER2)-positive ABC [4–6].

These guidelines are intended for use by infectious disease specialists, orthopedic surgeons, neurosurgeons, radiologists, and other healthcare professionals who care for patients with native vertebral osteomyelitis (NVO). They include evidence and opinion-based recommendations for the diagnosis and management of patients with NVO treated with antimicrobial therapy, with or without surgical intervention.

Nitrate in serum and urine was assayed by a modification of the cadmium-reduction method; the nitrite produced was determined by diazotization of sulfanilamide and coupling to naphthylethylene diamine. After samples were deproteinized with Somogyi reagent, the nitrate was reduced by Cu-coated Cd in glycine buffer at pH 9.7 (2.5 to 3 g of Cd granules for a 4-mL reaction mixture). The reduction followed pseudo-first-order reaction kinetics, a convenient time interval for assay being 75 to 90 min. Maximum reduction (85%) occurred at about 2 h. Detection limits in urine or serum were 2 to 250 mumol/L. This method does not require the reaction to go to completion, does not require expensive reagents or equipment, and can assay several samples simultaneously. Repeated assays of two serum pools gave CVs of 9.0% and 4.7% for nitrate concentrations of 31.4 and 80.2 mumol/L, respectively (n = 20 each). The mean concentration of nitrate was 1704.0 +/- 1294 (SD) mumol/L (n = 21) in untimed normal urine, 81.8 +/- 50.1 mumol/L in serum of 38 renal dialysis patients, and 51.2 +/- 26.4 mumol/L in serum of 38 controls.

OBJECTIVE: To clarify the grading of recommendations assessment, development and evaluation (GRADE) definition of certainty of evidence and suggest possible approaches to rating certainty of the evidence for systematic reviews, health technology assessments, and guidelines. STUDY DESIGN AND SETTING: This work was carried out by a project group within the GRADE Working Group, through brainstorming and iterative refinement of ideas, using input from workshops, presentations, and discussions at GRADE Working Group meetings to produce this document, which constitutes official GRADE guidance. RESULTS: Certainty of evidence is best considered as the certainty that a true effect lies on one side of a specified threshold or within a chosen range. We define possible approaches for choosing threshold or range. For guidelines, what we call a fully contextualized approach requires simultaneously considering all critical outcomes and their relative value. Less-contextualized approaches, more appropriate for systematic reviews and health technology assessments, include using specified ranges of magnitude of effect, for example, ranges of what we might consider no effect, trivial, small, moderate, or large effects. CONCLUSION: It is desirable for systematic review authors, guideline panelists, and health technology assessors to specify the threshold or ranges they are using when rating the certainty in evidence.

When formulating the relevant questions, panels should specify the patients, intervention, comparison, and outcomes (PICO), 9 their perspective, subgroups for which the evidence and their judgments and recommendation might differ from an overall recommendation, and the settings for which the recommendation is intended.

This position statement from the Heart Failure Association of the European Society of Cardiology Cardio-Oncology Study Group in collaboration with the International Cardio-Oncology Society presents practical, easy-to-use and evidence-based risk stratification tools for oncologists, haemato-oncologists and cardiologists to use in their clinical practice to risk stratify oncology patients prior to receiving cancer therapies known to cause heart failure or other serious cardiovascular toxicities. Baseline risk stratification proformas are presented for oncology patients prior to receiving the following cancer therapies: anthracycline chemotherapy, HER2-targeted therapies such as trastuzumab, vascular endothelial growth factor inhibitors, second and third generation multi-targeted kinase inhibitors for chronic myeloid leukaemia targeting BCR-ABL, multiple myeloma therapies (proteasome inhibitors and immunomodulatory drugs), RAF and MEK inhibitors or androgen deprivation therapies. Applying these risk stratification proformas will allow clinicians to stratify cancer patients into low, medium, high and very high risk of cardiovascular complications prior to starting treatment, with the aim of improving personalised approaches to minimise the risk of cardiovascular toxicity from cancer therapies.

Following approval of the ICD-11 by the World Health Assembly in May 2019, World Health Organization (WHO) member states will transition from the ICD-10 to the ICD-11, with reporting of health statistics based on the new system to begin on January 1, 2022. The WHO Department of Mental Health and Substance Abuse will publish Clinical Descriptions and Diagnostic Guidelines (CDDG) for ICD-11 Mental, Behavioural and Neurodevelopmental Disorders following ICD-11's approval. The development of the ICD-11 CDDG over the past decade, based on the principles of clinical utility and global applicability, has been the most broadly international, multilingual, multidisciplinary and participative revision process ever implemented for a classification of mental disorders. Innovations in the ICD-11 include the provision of consistent and systematically characterized information, the adoption of a lifespan approach, and culture-related guidance for each disorder. Dimensional approaches have been incorporated into the classification, particularly for personality disorders and primary psychotic disorders, in ways that are consistent with current evidence, are more compatible with recovery-based approaches, eliminate artificial comorbidity, and more effectively capture changes over time. Here we describe major changes to the structure of the ICD-11 classification of mental disorders as compared to the ICD-10, and the development of two new ICD-11 chapters relevant to mental health practice. We illustrate a set of new categories that have been added to the ICD-11 and present the rationale for their inclusion. Finally, we provide a description of the important changes that have been made in each ICD-11 disorder grouping. This information is intended to be useful for both clinicians and researchers in orienting themselves to the ICD-11 and in preparing for implementation in their own professional contexts.

Importance: Extended-spectrum β-lactamases mediate resistance to third-generation cephalosporins (eg, ceftriaxone) in Escherichia coli and Klebsiella pneumoniae. Significant infections caused by these strains are usually treated with carbapenems, potentially selecting for carbapenem resistance. Piperacillin-tazobactam may be an effective "carbapenem-sparing" option to treat extended-spectrum β-lactamase producers. Objectives: To determine whether definitive therapy with piperacillin-tazobactam is noninferior to meropenem (a carbapenem) in patients with bloodstream infection caused by ceftriaxone-nonsusceptible E coli or K pneumoniae. Design, Setting, and Participants: Noninferiority, parallel group, randomized clinical trial included hospitalized patients enrolled from 26 sites in 9 countries from February 2014 to July 2017. Adult patients were eligible if they had at least 1 positive blood culture with E coli or Klebsiella spp testing nonsusceptible to ceftriaxone but susceptible to piperacillin-tazobactam. Of 1646 patients screened, 391 were included in the study. Interventions: Patients were randomly assigned 1:1 to intravenous piperacillin-tazobactam, 4.5 g, every 6 hours (n = 188 participants) or meropenem, 1 g, every 8 hours (n = 191 participants) for a minimum of 4 days, up to a maximum of 14 days, with the total duration determined by the treating clinician. Main Outcomes and Measures: The primary outcome was all-cause mortality at 30 days after randomization. A noninferiority margin of 5% was used. Results: Among 379 patients (mean age, 66.5 years; 47.8% women) who were randomized appropriately, received at least 1 dose of study drug, and were included in the primary analysis population, 378 (99.7%) completed the trial and were assessed for the primary outcome. A total of 23 of 187 patients (12.3%) randomized to piperacillin-tazobactam met the primary outcome of mortality at 30 days compared with 7 of 191 (3.7%) randomized to meropenem (risk difference, 8.6% [1-sided 97.5% CI, -∞ to 14.5%]; P = .90 for noninferiority). Effects were consistent in an analysis of the per-protocol population. Nonfatal serious adverse events occurred in 5 of 188 patients (2.7%) in the piperacillin-tazobactam group and 3 of 191 (1.6%) in the meropenem group. Conclusions and relevance: Among patients with E coli or K pneumoniae bloodstream infection and ceftriaxone resistance, definitive treatment with piperacillin-tazobactam compared with meropenem did not result in a noninferior 30-day mortality. These findings do not support use of piperacillin-tazobactam in this setting. Trial Registration: anzctr.org.au Identifiers: ACTRN12613000532707 and ACTRN12615000403538 and ClinicalTrials.gov Identifier: NCT02176122.

Primary hyperparathyroidism is a common endocrine disease in those countries where multichannel screening is in common use, and hypercalcemia is readily detected. As a result of the introduction of the automated serum screening chemistry panel in the United States in the early 1970s, the prevalence and incidence of the disease were found to be much higher than previous estimates. In addition, the clinical profile had shifted from a symptomatic disorder, with hypercalcemic symptoms, kidney stones, overt bone disease, or a specific neuromuscular dysfunction, toward a more asymptomatic state. The modern clinical profile of asymptomatic primary hyperparathyroidism is best characterized as a disorder in which there are neither signs nor symptoms typically associated with hypercalcemia or parathyroid hormone excess. In light of the shift in the clinical profile of primary hyperparathyroidism, it was no longer clear whether parathyroid surgery was a necessary recommendation for all patients with this disease. Other issues related to medical management, surveillance, and defining criteria for diagnosis as well as the recommendation for surgery all led to the convening of a Consensus Development Conference on the Management of Asymptomatic Primary Hyperparathyroidism. This Conference, held at the NIH on October 29–31, 1990, was sponsored by the Office of Medical Applications of Research and the NIDDK. The recommendations of the panel of experts constituted then to review the evidence presented by authorities in the field led to a set of principles and guidelines for diagnosis as well as for surgical vs. nonoperative medical management of patients with asymptomatic primary hyperparathyroidism. Surgery was recognized as the only definitive therapy for primary hyperparathyroidism and was acknowledged to be virtually always an appropriate course of action. In particular, it was clear that any individual with overt complications of primary hyperparathyroidism, and therefore symptomatic (i.e. renal stones, fractures, or neuromuscular syndrome), should have parathyroid surgery. It was also emphasized that in many patients with primary hyperparathyroidism, there were no signs or symptoms commonly associated with the disease. Even though these individuals were asymptomatic, a number of features were identified as possible risk factors for the development of complications of primary hyperparathyroidism. It was recommended that surgery be performed if any of the following indications were present: 1) serum calcium concentration of 1–1.6 mg/dl (0.25–0.4 mm) above the accepted normal reference range; 2) confirmed 24-h total urinary calcium excretion of more than 400 mg (10 mmol); 3) creatinine clearance reduced by 30% compared with age-matched normal subjects; 4) bone mineral density reduced by more than 2 sd below the bone density of age-, gender-, and race-matched control subjects; 5) patients under 50 yr of age; and 6) patients for whom medical surveillance was either not desirable (e.g. coexistent illness) or not possible. The Consensus Development Panel noted that there was a large subgroup of patients who could be followed safely without surgery if they did not meet any of the aforementioned criteria. The Panel commented on patients who may have one or more vague symptoms, especially related to the neurobehavioral axis. The nonspecific nature of these symptoms (weakness and easy fatigability in the absence of overt muscle weakness) led to the recommendation that these symptoms were not sufficient in and of themselves to lead to a recommendation for surgery unless it was perceived that these complaints were indeed related to hyperparathyroidism. The Panel recommended that patients who were not to have parathyroid surgery be monitored on a regular basis. It was considered important that the patient understand the importance of regular, conscientious, long-term monitoring, the goals of which included early recognition of worsening hypercalcemia, loss of bone mass, renal impairment, renal stones, or fractures. To this end, biannual visits were recommended at which blood pressure, serum calcium concentration, serum creatinine, and creatinine clearance would be measured. In addition, on an annual basis, abdominal radiographs (and/or ultrasound), a 24-h urine collection for calcium, and bone mass measurements were advised. The intervals between these measurements could be lengthened after it was established that the patient was showing no changes in any of the indexes being monitored. Focused medical therapy for the management of primary hyperparathyroidism was not recommended based on lack of evidence for efficacy, but the importance of hydration, adequate mobility, and a diet that was neither restricted nor excessive in calcium was acknowledged. Prompt medical attention for the possibility of worsening hypercalcemia was urged in the event of any serious intercurrent illness accompanied by a risk of dehydration. Since 1990, many studies have shed new light on the issues considered by the Consensus Development Panel. Considerable data have accumulated on the natural history of asymptomatic primary hyperparathyroidism with or without surgery. We have greater knowledge of bone involvement in primary hyperparathyroidism by use of cross-sectional and prospective studies with dual energy x-ray absorptiometry. Significant advances in surgery, particularly minimally invasive approaches, and in preoperative localization of parathyroid adenomas have occurred. Promising medical therapies for primary hyperparathyroidism have been introduced. In addition, there have been concerns about cardiovascular risk and other atypical manifestations of primary hyperparathyroidism. For these reasons, it was deemed appropriate to convene another conference on this subject with a view to reevaluating the conclusions of the 1990 Consensus Development Panel. Accordingly, a Workshop on Asymptomatic Primary Hyperparathyroidism: A Perspective for the 21st Century was held at the NIH on April 8–9, 2002. It was sponsored by the NIDDK. The Workshop was cosponsored by the NIAMS, The Endocrine Society, The Paget Foundation for Paget’s of and of and Office of Research on Office of of of for and and the were by experts who a of issues related to primary hyperparathyroidism. The included the of primary hyperparathyroidism in the United and other of the and clinical in the United and other of the bone mass natural new surgical and localization and new to specific medical management of primary hyperparathyroidism. the Workshop was to an end, a of with and in primary hyperparathyroidism to of issues identified by the 1990 Consensus Development Conference have of this disease. the of experts considered if should be recommended for who for patients with primary hyperparathyroidism. This a of the of this the of which were and this was to all Workshop and changes were This Panel was not constituted or by the primary of the the NIH and the NIDDK. The of the Panel was not on symptomatic primary hyperparathyroidism, in which patients with complications of the disease, as bone disease, fractures, renal stones, or overt neuromuscular patients should always be to the Panel considered to asymptomatic primary hyperparathyroidism in the United but the of was and of the following asymptomatic primary hyperparathyroidism to patients in other countries is not Primary hyperparathyroidism is by hypercalcemia in the of normal of that could be associated with hypercalcemia, as and should be if and the patient The for the of patients with primary hyperparathyroidism have In patients with primary hyperparathyroidism, the be in the of which is with the diagnosis of primary hyperparathyroidism hypercalcemia is The normal for the not the that with and between and In normal are typically higher than those in the other are typically in It was recommended that for and for and calcium would be A for been that to only the The also of a large of that is a of the of the It is not whether the in which large hormone are not in this is especially in view of evidence that hypercalcemia also to in the as hypercalcemia is a disorder that also with hypercalcemia and or normal as a of atypical primary hyperparathyroidism, it is a that be by parathyroid surgery. be from primary hyperparathyroidism. in an is in but not to a in the that is the of parathyroid to The for a of urine calcium and of the clearance in the patient and with In the clearance is typically than In primary hyperparathyroidism, the clearance is typically greater than It is important to between primary hyperparathyroidism and in the parathyroid surgery is not the disorder is with hyperparathyroidism a surgical in which total is for of a would readily between and primary hyperparathyroidism in Primary hyperparathyroidism also as of endocrine but these patients a of patients with primary hyperparathyroidism. This possibility should be in of a history of hypercalcemia or other endocrine and primary hyperparathyroidism in The diagnosis should be to clinical for specific may as for the all patients with primary hyperparathyroidism have hypercalcemia serum calcium is measured. It is common for patients with primary hyperparathyroidism and hypercalcemic mg/dl above the of to have normal serum calcium on In serum calcium is in the of the normal In a number of only calcium is In other neither total nor calcium is patients with normal serum calcium are being is in the course of for or in the of for are as patients with primary hyperparathyroidism. This that all of of be particularly calcium to a disorder, renal by serum of or of renal The for primary hyperparathyroidism should typically a of the that are to be by primary the and the As be the is best by bone dual energy x-ray absorptiometry. are no longer patients in the United States are to of primary hyperparathyroidism. As kidney are the common of primary hyperparathyroidism, a with renal abdominal is the 24-h urinary calcium be not only in to between primary hyperparathyroidism and but also in a of the renal for urinary calcium excretion is not well with the risk of kidney stones, it be as a urinary creatinine excretion with the serum creatinine concentration an of creatinine the been in of the guidelines at the Consensus Development Conference of 1990 may or may not be to at this the of surgery or no surgery in primary hyperparathyroidism. of those guidelines is with about the recommendations for As at the Consensus Development Conference, there are many of in the of a total serum calcium is also a to reference and to of in the should be serum calcium should be to the serum For in the serum concentration from the the serum calcium concentration should be by The Panel considered the of an serum calcium concentration as it the and is the of by of the calcium concentration was not recommended by the panel not have to a that it As there is greater reference for the total serum calcium concentration, it is to on the total serum calcium The for the total serum calcium concentration to be as a for surgery was set at mg/dl mm) above the of normal for that may be asymptomatic of hypercalcemia serum calcium is greater than mg/dl above but the panel of experts it to the from 1–1.6 to mg/dl above normal patients above this new may be at greater risk for symptomatic hyperparathyroidism and for complications of the disease. The recommendation is serum calcium greater than mg/dl above the of The recommendation that the urinary calcium be as an for of surgery from the that urinary calcium excretion above 400 is a risk for the development of kidney or may a higher of bone The Panel emphasized the importance of other urinary as urinary as a to with more urinary calcium excretion been to be a of risk those who have had a kidney The 24-h urinary calcium excretion the of calcium calcium calcium and the serum calcium is to and and issues related to of the collection The urinary is more to calcium but it is not as an of bone in primary hyperparathyroidism as are the specific bone and a of urinary calcium excretion a of the calcium on the kidney to a of these 24-h urinary calcium is at the of the of the Workshop that it should be considered a in parathyroid surgery. The mg in is well above the of normal and to in urinary calcium to and it may be important to this number in to the that typically more calcium than typically calcium than The Panel that if urinary calcium excretion was not excessive at the of the then with an annual 24-h urinary calcium was not The recommendation is 24-h urinary calcium greater than 400 The Panel acknowledged that renal could be in primary hyperparathyroidism. It with the to renal and recognized that the of creatinine clearance is and to in the with the 24-h urinary calcium, the creatinine is with to the clearance and creatinine clearance is therefore recommended in the of the patient with primary hyperparathyroidism. it is more than 30% reduced from and control the Panel that surgery should be advised. creatinine a of creatinine clearance the is creatinine The serum creatinine is recommended in those patients who not have reduced renal at and are to be monitored without surgery on The recommendation is creatinine clearance reduced by more than 30% compared with age-matched more is about bone mineral density in primary hyperparathyroidism, dual energy x-ray a in the of bone mass these In patients with asymptomatic primary hyperparathyroidism, the of bone loss the of being more at in bone (i.e. the one than in bone (i.e. the It been but not that a in bone mineral density in primary hyperparathyroidism risk to a as in bone mineral density in without primary hyperparathyroidism. data would to this at there are no prospective data to this the of this the Panel recommended a from the to the as a for surgical The that the be as a was based on the that it the of the disease on bone mass, as the the of in bone mineral density from and if bone mass measurements risk to the in primary hyperparathyroidism as they in other it more in to use the which from bone The Panel also recommended that in to of the one density and density be in primary hyperparathyroidism. bone density more the of a of patients with primary hyperparathyroidism have more in the than at other studies that risk is in primary hyperparathyroidism, but these studies are of cross-sectional nature and issues of possible the in bone mass at of bone after more for a in in bone mass at any in this disease. these the Panel that patients be to surgery if the at the or is below This is with of established by the and other of other as or are not there are data on these of in primary hyperparathyroidism. there are about to reference in the the Panel that and race-matched should be possible. For with primary hyperparathyroidism would be compared with the established for are not as in the of should use the for As to surgery to be it is possible that this recommendation for surgery, based the could be specific medical are to be associated with in bone The recommendation is bone density at the or that is more than sd below bone mass The panel new evidence the that patients who are under the of 50 yr are at greater risk for complications in primary hyperparathyroidism. evidence than 50 yr as a risk for complications of primary hyperparathyroidism, as reduced bone mineral This evidence to individuals under the of 50 yr who meet or not meet other noted guidelines for surgery. The recommendation is individuals with primary hyperparathyroidism under the of 50 yr should be for surgery. The Panel recognized that patients with primary hyperparathyroidism who not meet any guidelines for surgery would to one or more criteria. is if patients are not to have a patient with asymptomatic primary hyperparathyroidism be followed for any the Panel that this is sufficient to parathyroid surgery at the the diagnosis of primary hyperparathyroidism is The recommendation is The Panel considered other possible as dysfunction, cardiovascular symptoms, and serum or urinary indexes of bone that could the in asymptomatic primary hyperparathyroidism. of the of the factors below for the disease under the Panel that they should not be as criteria for surgery. the clinical the to in the of the clinical are data primary hyperparathyroidism with and easy fatigability the absence of overt and In addition, have on in primary hyperparathyroidism that of of The panel acknowledged that in of these indexes been after but also noted that it is not possible at this to which patients The of in patients with primary hyperparathyroidism to the bone loss that in early without primary hyperparathyroidism. in this not to from bone loss to This should be considered in early who not meet other criteria for surgery. To the that there are data asymptomatic primary hyperparathyroidism in the United States is not associated with overt cardiovascular in patients with the serum calcium were at risk for all of This may be with of cardiovascular from where the disease is more is not after parathyroid surgery and therefore should not be considered an for Asymptomatic primary hyperparathyroidism in the United States is not associated with disease it is associated with endocrine or therefore should not be as criteria for surgery in primary hyperparathyroidism. the panel recognized the of bone in the of in primary hyperparathyroidism, it is not clear that of bone are of the of bone loss or as they are in individuals without primary hyperparathyroidism. Asymptomatic primary hyperparathyroidism is associated with of bone and that may be at the of normal or A of the indications for surgery recommended by the 1990 Consensus Development Panel and the recommendations by the Primary is in A of new and guidelines for parathyroid surgery in asymptomatic primary hyperparathyroidism Surgery is also in patients for whom medical surveillance is neither nor possible. A of new and guidelines for parathyroid surgery in asymptomatic primary hyperparathyroidism Surgery is also in patients for whom medical surveillance is neither nor possible. The Panel with the previous recommendations that for asymptomatic primary hyperparathyroidism, there are no medical therapies for which data are either or may be in early for the they are recommended by for who not have primary hyperparathyroidism. As specific therapy for the hypercalcemia of primary hyperparathyroidism, the Panel to that may the serum calcium but is not of are that are higher than or would The Panel was in new data of that have with to the medical management of asymptomatic primary hyperparathyroidism. The early data were the of and in primary hyperparathyroidism. The presented for all of was to showing on as serum calcium and bone but not on clinical data are these may in patients guidelines for surgery for one or a medical may also in patients for whom surgery is not a primary The importance of sufficient calcium was is no for restricted in calcium in this disease. In there may be to be that restricted calcium the associated with of there is for in The is to to the for calcium for in the United The importance of was also In primary hyperparathyroidism, of below could the associated with In individuals are below this it is to would to be but the serum calcium concentration be monitored on the that in patients serum calcium could The Panel recognized that patients with asymptomatic primary hyperparathyroidism not meet any of the recommended criteria for surgery, it emphasized that surgery is the only definitive for this disease. The Panel also that there are patients for whom surgery not be accepted as a as well as the that there are other patients for whom medical issues for a surgical patients with asymptomatic primary hyperparathyroidism signs of the The of to worsening disease be identified at the of is if patients are not to parathyroid surgery. The serum calcium concentration should be mass measurements at all and are recommended on a basis. The Panel between the of the patient and the recommendations for with specific reference to renal For the Panel to to abdominal radiographs or to and an of urinary calcium and creatinine the Panel no to measurements of the urinary calcium, creatinine or studies for in those patients who did not meet renal criteria for surgery. it was considered to serum creatinine on a basis, with an of creatinine clearance by the serum creatinine concentration and of the A of indexes recommended by the 1990 Consensus Development Panel for patients who are not to have surgery and the recommendations by the Panel is in A of new and management guidelines for patients with asymptomatic primary hyperparathyroidism who not parathyroid surgery at the of the the serum creatinine concentration a in the creatinine the is more of the creatinine clearance are A of new and management guidelines for patients with asymptomatic primary hyperparathyroidism who not parathyroid surgery at the of the the serum creatinine concentration a in the creatinine the is more of the creatinine clearance are The Panel emphasized the for to be performed by who are and in the The for is of the with of all parathyroid The for all is that in of patients with primary hyperparathyroidism, of more than one be advances in the use of have led many parathyroid to with than A of minimally invasive have been introduced. of the minimally invasive is performed with preoperative localization is for primary hyperparathyroidism and only if a is The of and under of the without of other by the and after the is an is to that the is the only of be performed and not the of the after of the the by greater than the is the not by greater than the is and if a is performed to other with the for primary hyperparathyroidism, to This surgical could the of if long-term patient early and to the As is for the a and parathyroid The Panel with the of the by the at the Consensus Development Conference in 1990 that the in preoperative localization of the parathyroid is an parathyroid was that should be performed only by parathyroid in should be the of parathyroid advances in of parathyroid have led many to use preoperative localization preoperative localization is the is localization should not be to or the diagnosis of primary hyperparathyroidism. The localization is with In the this to of parathyroid In that are not as this to Other as and be at Even in no or of studies a localization than the parathyroid who typically of In the patient who had previous surgery, the Panel emphasized the to the diagnosis of primary hyperparathyroidism and confirmed the at the Consensus Development Conference that preoperative studies be The should be the with possible. Other as and be It is to patients with previous surgery to with the to and these localization and with measurements of from of the are best for those patients in whom all localization have In from the with these localization in patients who have had previous surgery the as those who have not had previous surgery. In to surgical as the use of with and have been found to be in but to be in primary hyperparathyroidism the led to a of important that the Panel for the is for more about the of primary hyperparathyroidism in the United especially with to with which be and and prevalence the in A of patients with primary hyperparathyroidism be in this of the natural history of primary hyperparathyroidism should to of this disease not only with patients who are monitored without or after but also with patients in whom specific medical therapies are The and of primary hyperparathyroidism to be with to that have been identified as well as by which the development of the be being should the of in patients with hyperparathyroidism may other between of a parathyroid and other that lead to be of importance to The of for in the diagnosis of primary hyperparathyroidism be with to the recognized of The of vs. that only should be in the diagnosis of primary hyperparathyroidism, the of hyperparathyroidism, and the of parathyroid surgery. 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It is with from the of and minimally invasive

Vitamin D deficiency (serum 25-hydroxyvitamin D (25(OH)D) <50 nmol/L or 20 ng/mL) is common in Europe and the Middle East. It occurs in <20% of the population in Northern Europe, in 30-60% in Western, Southern and Eastern Europe and up to 80% in Middle East countries. Severe deficiency (serum 25(OH)D <30 nmol/L or 12 ng/mL) is found in >10% of Europeans. The European Calcified Tissue Society (ECTS) advises that the measurement of serum 25(OH)D be standardized, for example, by the Vitamin D Standardization Program. Risk groups include young children, adolescents, pregnant women, older people (especially the institutionalized) and non-Western immigrants. Consequences of vitamin D deficiency include mineralization defects and lower bone mineral density causing fractures. Extra-skeletal consequences may be muscle weakness, falls and acute respiratory infection, and are the subject of large ongoing clinical trials. The ECTS advises to improve vitamin D status by food fortification and the use of vitamin D supplements in risk groups. Fortification of foods by adding vitamin D to dairy products, bread and cereals can improve the vitamin D status of the whole population, but quality assurance monitoring is needed to prevent intoxication. Specific risk groups such as infants and children up to 3 years, pregnant women, older persons and non-Western immigrants should routinely receive vitamin D supplements. Future research should include genetic studies to better define individual vulnerability for vitamin D deficiency, and Mendelian randomization studies to address the effect of vitamin D deficiency on long-term non-skeletal outcomes such as cancer.

Bisphosphonates (BPs) are the most commonly used medications for osteoporosis. This ASBMR report provides guidance on BP therapy duration with a risk-benefit perspective. Two trials provided evidence for long-term BP use. In the Fracture Intervention Trial Long-term Extension (FLEX), postmenopausal women receiving alendronate for 10 years had fewer clinical vertebral fractures than those switched to placebo after 5 years. In the HORIZON extension, women who received 6 annual infusions of zoledronic acid had fewer morphometric vertebral fractures compared with those switched to placebo after 3 years. Low hip T-score, between -2 and -2.5 in FLEX and below -2.5 in HORIZON extension, predicted a beneficial response to continued therapy. Hence, the Task Force suggests that after 5 years of oral BP or 3 years of intravenous BP, reassessment of risk should be considered. In women at high risk, for example, older women, those with a low hip T-score or high fracture risk score, those with previous major osteoporotic fracture, or who fracture on therapy, continuation of treatment for up to 10 years (oral) or 6 years (intravenous), with periodic evaluation, should be considered. The risk of atypical femoral fracture, but not osteonecrosis of the jaw, clearly increases with BP therapy duration, but such rare events are outweighed by vertebral fracture risk reduction in high-risk patients. For women not at high fracture risk after 3 to 5 years of BP treatment, a drug holiday of 2 to 3 years can be considered. The suggested approach for long-term BP use is based on limited evidence, only for vertebral fracture reduction, in mostly white postmenopausal women, and does not replace the need for clinical judgment. It may be applicable to men and patients with glucocorticoid-induced osteoporosis, with some adaptations. It is unlikely that future trials will provide data for formulating definitive recommendations. © 2015 American Society for Bone and Mineral Research.

BACKGROUND: In advanced prostate cancer (APC), successful drug development as well as advances in imaging and molecular characterisation have resulted in multiple areas where there is lack of evidence or low level of evidence. The Advanced Prostate Cancer Consensus Conference (APCCC) 2017 addressed some of these topics. OBJECTIVE: To present the report of APCCC 2017. DESIGN, SETTING, AND PARTICIPANTS: Ten important areas of controversy in APC management were identified: high-risk localised and locally advanced prostate cancer; "oligometastatic" prostate cancer; castration-naïve and castration-resistant prostate cancer; the role of imaging in APC; osteoclast-targeted therapy; molecular characterisation of blood and tissue; genetic counselling/testing; side effects of systemic treatment(s); global access to prostate cancer drugs. A panel of 60 international prostate cancer experts developed the program and the consensus questions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The panel voted publicly but anonymously on 150 predefined questions, which have been developed following a modified Delphi process. RESULTS AND LIMITATIONS: Voting is based on panellist opinion, and thus is not based on a standard literature review or meta-analysis. The outcomes of the voting had varying degrees of support, as reflected in the wording of this article, as well as in the detailed voting results recorded in Supplementary data. CONCLUSIONS: The presented expert voting results can be used for support in areas of management of men with APC where there is no high-level evidence, but individualised treatment decisions should as always be based on all of the data available, including disease extent and location, prior therapies regardless of type, host factors including comorbidities, as well as patient preferences, current and emerging evidence, and logistical and economic constraints. Inclusion of men with APC in clinical trials should be strongly encouraged. Importantly, APCCC 2017 again identified important areas in need of trials specifically designed to address them. PATIENT SUMMARY: The second Advanced Prostate Cancer Consensus Conference APCCC 2017 did provide a forum for discussion and debates on current treatment options for men with advanced prostate cancer. The aim of the conference is to bring the expertise of world experts to care givers around the world who see less patients with prostate cancer. The conference concluded with a discussion and voting of the expert panel on predefined consensus questions, targeting areas of primary clinical relevance. The results of these expert opinion votes are embedded in the clinical context of current treatment of men with advanced prostate cancer and provide a practical guide to clinicians to assist in the discussions with men with prostate cancer as part of a shared and multidisciplinary decision-making process.

Despite advances in preventive, diagnostic, and therapeutic interventions, invasive fungal infections cause significant morbidity and mortality in immunocompromised patients. The burden of antifungal resistance in such high-risk patients is becoming a major concern. A better understanding of the mechanisms and clinical impact of antifungal resistance is essential to the prompt and efficient treatment of patients with invasive mycoses and to improving the outcome of such infections. Although recent guidelines have attempted to standardize antifungal susceptibility testing, limitations still exist as a result of the incomplete correlation between in vitro susceptibility and clinical response to treatment. Four major mechanisms of resistance to azoles have been identified, all of which rely on altered gene expression. Mechanisms responsible for polyene and echinocandin resistance are less well understood. In addition to discussing the molecular mechanisms of antifungal resistance, this article elaborates on the concept of clinical resistance, which is critical to the understanding of treatment failure in patients with invasive fungal infections.

BACKGROUND: Deoxygenated sickle hemoglobin (HbS) polymerization drives the pathophysiology of sickle cell disease. Therefore, direct inhibition of HbS polymerization has potential to favorably modify disease outcomes. Voxelotor is an HbS polymerization inhibitor. METHODS: In a multicenter, phase 3, double-blind, randomized, placebo-controlled trial, we compared the efficacy and safety of two dose levels of voxelotor (1500 mg and 900 mg, administered orally once daily) with placebo in persons with sickle cell disease. The primary end point was the percentage of participants who had a hemoglobin response, which was defined as an increase of more than 1.0 g per deciliter from baseline at week 24 in the intention-to-treat analysis. RESULTS: -thalassemia), and approximately two thirds were receiving hydroxyurea at baseline. In the intention-to-treat analysis, a significantly higher percentage of participants had a hemoglobin response in the 1500-mg voxelotor group (51%; 95% confidence interval [CI], 41 to 61) than in the placebo group (7%; 95% CI, 1 to 12). Anemia worsened between baseline and week 24 in fewer participants in each voxelotor dose group than in those receiving placebo. At week 24, the 1500-mg voxelotor group had significantly greater reductions from baseline in the indirect bilirubin level and percentage of reticulocytes than the placebo group. The percentage of participants with an adverse event that occurred or worsened during the treatment period was similar across the trial groups. Adverse events of at least grade 3 occurred in 26% of the participants in the 1500-mg voxelotor group, 23% in the 900-mg voxelotor group, and 26% in the placebo group. Most adverse events were not related to the trial drug or placebo, as determined by the investigators. CONCLUSIONS: In this phase 3 randomized, placebo-controlled trial involving participants with sickle cell disease, voxelotor significantly increased hemoglobin levels and reduced markers of hemolysis. These findings are consistent with inhibition of HbS polymerization and indicate a disease-modifying potential. (Funded by Global Blood Therapeutics; HOPE ClinicalTrials.gov number, NCT03036813.).

BACKGROUND: The appropriate caloric goal for critically ill adults is unclear. We evaluated the effect of restriction of nonprotein calories (permissive underfeeding), as compared with standard enteral feeding, on 90-day mortality among critically ill adults, with maintenance of the full recommended amount of protein in both groups. METHODS: At seven centers, we randomly assigned 894 critically ill adults with a medical, surgical, or trauma admission category to permissive underfeeding (40 to 60% of calculated caloric requirements) or standard enteral feeding (70 to 100%) for up to 14 days while maintaining a similar protein intake in the two groups. The primary outcome was 90-day mortality. RESULTS: Baseline characteristics were similar in the two groups; 96.8% of the patients were receiving mechanical ventilation. During the intervention period, the permissive-underfeeding group received fewer mean (±SD) calories than did the standard-feeding group (835±297 kcal per day vs. 1299±467 kcal per day, P<0.001; 46±14% vs. 71±22% of caloric requirements, P<0.001). Protein intake was similar in the two groups (57±24 g per day and 59±25 g per day, respectively; P=0.29). The 90-day mortality was similar: 121 of 445 patients (27.2%) in the permissive-underfeeding group and 127 of 440 patients (28.9%) in the standard-feeding group died (relative risk with permissive underfeeding, 0.94; 95% confidence interval [CI], 0.76 to 1.16; P=0.58). No serious adverse events were reported; there were no significant between-group differences with respect to feeding intolerance, diarrhea, infections acquired in the intensive care unit (ICU), or ICU or hospital length of stay. CONCLUSIONS: Enteral feeding to deliver a moderate amount of nonprotein calories to critically ill adults was not associated with lower mortality than that associated with planned delivery of a full amount of nonprotein calories. (Funded by the King Abdullah International Medical Research Center; PermiT Current Controlled Trials number, ISRCTN68144998.).