A safety evaluation of intermittent high-dose inhaled nitric oxide in viral pneumonia due to COVID-19: a randomised clinical study.

High-dose inhaled Nitric Oxide (iNO) has been shown to have anti-inflammatory, vasodilator, and antimicrobial properties, resulting in improved arterial oxygenation as well as a beneficial therapeutic effect on lower respiratory tract infections. This study evaluated the safety and efficacy of 150-ppm intermittent iNO administered with a novel iNO-generator, for treating adults hospitalised for viral pneumonia. In this prospective, open-label, multicenter study, subjects aged 18-80, diagnosed with viral pneumonia received either standard supportive treatment alone (Control-Group) or combined with iNO for 40 min, 4 times per day up to 7 days (Treatment-Group). Out of 40 recruited subjects, 35 were included in the intention-to-treat population (34 with COVID-19). Adverse Events rate was similar between the groups (56.3% vs. 42.1%; respectively). No treatment-related adverse events were reported, while 2 serious adverse events were accounted for by underlying pre-existing conditions. Among the Treatment-Group, oxygen support duration was reduced by 2.7 days (Hazard Ratio = 2.8; p = 0.0339), a greater number of subjects reached oxygen saturation ≥ 93% within hospitalisation period (Hazard Ratio = 5.4; p = 0.049), and a trend for earlier discharge was demonstrated. Intermittent 150-ppm iNO-treatment is well-tolerated, safe, and beneficial compared to usual care for spontaneously breathing hospitalised adults diagnosed with COVID-19 viral pneumonia.

Tall stature and gigantism in transition age: clinical and genetic aspects-a literature review and recommendations.

PURPOSE: Tall stature is defined as height greater than the threshold of more than 2 standard deviations above the average population height for age, sex, and ethnicity. Many studies have described the main aspects of this condition during puberty, but an analysis of the characteristics that the physician should consider in the differential diagnosis of gigantism-tall stature secondary to a pituitary tumour-during the transition age (15-25 years) is still lacking. METHODS: A comprehensive search of English-language original articles was conducted in the MEDLINE database (December 2021-March 2022). We selected all studies regarding epidemiology, genetic aspects, and the diagnosis of tall stature and gigantism during the transition age. RESULTS: Generally, referrals for tall stature are not as frequent as expected because most cases are familial and are usually unreported by parents and patients to endocrinologists. For this reason, lacking such experience of tall stature, familiarity with many rarer overgrowth syndromes is essential. In the transition age, it is important but challenging to distinguish adolescents with high constitutional stature from those with gigantism. Pituitary gigantism is a rare disease in the transition age, but its systemic complications are very relevant for future health. Endocrine evaluation is crucial for identifying conditions that require hormonal treatment so that they can be treated early to improve the quality of life and prevent comorbidities of individual patient in this age range. CONCLUSION: The aim of our review is to provide a practical clinical approach to recognise adolescents, potentially affected by gigantism, as early as possible.

An international simulated-use study to assess nurses' preferences between two lanreotide syringes for patients with neuroendocrine tumours or acromegaly (PRESTO 3).

PURPOSE: PRESTO 3 evaluated nurses' preference for the Somatuline® Autogel® syringe versus the Lanreotide Pharmathen syringe after injection-pad testing. METHODS: This international simulated-use study included oncology/endocrinology nurses with ≥ 1 years' experience in managing neuroendocrine tumours (NETs) and/or acromegaly. Each nurse tested both syringes twice in a randomised order before completing an electronic survey. The primary objective was to assess overall preference (%, 95% confidence interval [CI]) for the Somatuline Autogel syringe versus the Lanreotide Pharmathen syringe. Secondary objectives included rating syringe performance and ranking the importance of syringe attributes. RESULTS: Ninety-four nurses were enrolled: mean age, 41.0 (SD, 11.5) years. The percentage of nurses stating a preference ("strong" or "slight") for the Somatuline Autogel syringe (86.2% [95% CI 77.5-92.4%]) was significantly higher than 50% (p < 0.0001). Performance rating was significantly higher for the Somatuline Autogel syringe versus Lanreotide Pharmathen syringe for 10 of the 11 attributes tested (p < 0.05). The syringe attributes considered most important when injecting patients in routine clinical practice were "easy to use from preparation to injection" (30.9%) and "comfortable to handle during use from preparation to injection" (16.0%). The attribute most commonly rated as least important was "fast administration from preparation to injection" (26.6%). CONCLUSION: Nurses strongly preferred the user experience of the Somatuline Autogel syringe over the Lanreotide Pharmathen syringe. "Ease of use" and "comfortable to handle" were the most important syringe attributes, and performance rating was significantly higher with Somatuline Autogel versus Lanreotide Pharmathen syringe for all but one attribute.

Drugs called somatostatin analogues (SSAs) can be used to treat patients with neuroendocrine tumours or acromegaly over a prolonged period of time. SSAs are given as injections and act by slowing the production of hormones by the body and in some cases reducing the growth of the tumour. To help to provide the best care possible, it is important that the syringe used for the injection is easy to use and delivers the SSA effectively. Somatuline Autogel is a syringe that can be used to inject an SSA called lanreotide. Previous studies showed that patients and nurses preferred the injection experience when using the Somatuline Autogel syringe compared with a syringe used to inject another SSA called octreotide long-acting release. A new syringe used for lanreotide injections has been developed recently by a company called Pharmathen. In the PRESTO 3 study, we compared the user experience of the Somatuline Autogel syringe and the Lanreotide Pharmathen syringe. We asked 94 nurses from Europe and the US to test both syringes, in a randomised order, using injection pads, and then to answer questions about their overall preference between the two syringes and how well the syringe performed for a set of syringe features. Overall, 86% of nurses preferred the Somatuline Autogel syringe over the Lanreotide Pharmathen syringe. Of the 11 features of the syringe that we assessed, 10 were rated higher for the Somatuline Autogel syringe than the Lanreotide Pharmathen syringe. The syringe features "ease of use" and "comfortable to handle" were considered the most important. The results of the PRESTO 3 study indicated that there is a difference in the user experience between the syringes, particularly for confidence and ease of use, and that it is important to offer syringe choices to nurses who are using SSA injections to treat patients.

Sellar and parasellar lesions in the transition age: a retrospective Italian multi-centre study.

BACKGROUND: Sellar/parasellar lesions have been studied in the adult and paediatric age range, but during the transition age their epidemiology, clinical manifestations, management and treatment outcomes have been poorly investigated. MATERIALS AND METHODS: An Italian multicentre cohort study, in which hospital records of patients with diagnosis of sellar/parasellar lesions during the transition age and young adulthood (15-25 years), were reviewed in terms of prevalence, clinical and hormonal features at diagnosis, and outcomes where available. Both pituitary neuroendocrine tumours (pituitary tumours, Group A) and non-endocrine lesions (Group B) were included. RESULTS: Among Group A (n = 170, 46.5% macroadenomas), the most frequent were prolactin and GH-secreting tumours, with a female predominance. Among Group B (n = 28), germinomas and Rathke cells cysts were the most common. In Group A, the most frequent hormonal deficiency was gonadal dysfunction. Galactorrhoea and amenorrhoea were relatively common in female patients with prolactinomas. Pre-surgical diabetes insipidus was only seen in Group B, in which also hormone deficiencies were more frequent and numerous. Larger lesions were more likely to be seen in Group B. Patients in Group B were more frequently male, younger, and leaner than those of Group A, whereas at last follow-up they showed more obesity and dyslipidaemia. In our cohort, the percentage of patients with at least one pituitary deficiency increased slightly after surgery. CONCLUSIONS: The management of sellar/parasellar lesions is challenging in the transition age, requiring an integrated and multidisciplinary approach. Hormone and metabolic disorders can occur many years after treatment, therefore long-term follow-up is mandatory.

Metabolic control of acclimation to nutrient deprivation dependent on polyphosphate synthesis.

Polyphosphate, an energy-rich polymer conserved in all kingdoms of life, is integral to many cellular stress responses, including nutrient deprivation, and yet, the mechanisms that underlie its biological roles are not well understood. In this work, we elucidate the physiological function of this polymer in the acclimation of the model alga Chlamydomonas reinhardtii to nutrient deprivation. Our data reveal that polyphosphate synthesis is vital to control cellular adenosine 5'-triphosphate homeostasis and maintain both respiratory and photosynthetic electron transport upon sulfur deprivation. Using both genetic and pharmacological approaches, we show that electron flow in the energy-generating organelles is essential to induce and sustain acclimation to sulfur deprivation at the transcriptional level. These previously unidentified links among polyphosphate synthesis, photosynthetic and respiratory electron flow, and the acclimation of cells to nutrient deprivation could unveil the mechanism by which polyphosphate helps organisms cope with a myriad of stress conditions in a fluctuating environment.

Renin-angiotensin system inhibitors in management of hypertension during the COVID-19 pandemic.

COVID-19, which is caused by the single-stranded RNA severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has introduced significant therapeutic dilemmas in several areas. One of these is concern regarding the use of renin-angiotensin system (RAS) inhibitors. Dysfunction of the RAS has been observed in COVID-19 patients, but whether RAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs), are associated with improved or worse clinical outcomes, remains unclear. RAS inhibitors are currently widely used in the treatment of hypertension. Emerging data suggest an increased association and a heightened mortality in patients of COVID-19 with co-morbidities such as hypertension, coronary heart disease, and diabetes mellitus, particularly in the elderly. Therefore, several recently published research papers have focused on the management of hypertension during the COVID-19 pandemic, as this co-morbidity was found to be the most common in patients with coronavirus infections. SARS-CoV-2 viral surface protein is known to attach angiotensin converting enzyme-2 (ACE-2) on the cell membrane to facilitate viral entry into the cytoplasm. While the SARS-CoV-2 viral load remains the highest in upper respiratory tract of COVID-19 patients, it has also been reported in multiple sites in COVID-19, and patients not infrequently require the Intensive Care Units (ICU) admission. However, despite the theoretical concerns of possible increased ACE2 expression by RAS blockade, there is no evidence that RAS inhibitors are harmful during COVID-19 infection, and indeed they have been shown to be beneficial in some animal studies. In this review we summarise the pathophysiology of the interaction between RAS, ACEIs/ARBs inhibitors and COVID-19, and conclude, on the basis of current data, that RAS blockade should be maintained during the current coronavirus pandemic.

Hearing threshold shifts among military pilots of the Israeli Air Force.

BACKGROUND: Military aviators are potentially at risk for developing noise-induced hearing loss. Whether ambient aircraft noise exposure causes hearing deficit beyond the changes attributed to natural ageing is debated. The aim of this research was to assess changes in hearing thresholds of Israeli Air Force (IAF) pilots over 20 years of military service and identify potential risk factors for hearing loss. METHODS: A retrospective cohort analysis was conducted of pure-tone air conduction audiograms of pilots, from their recruitment at 18 years of age until the last documented medical check-up. Mean hearing thresholds were analysed in relation to age, total flight hours and aircraft platform. Comparisons were made to the hearing thresholds of air traffic controllers (ATCs) who were not exposed to the noise generated by aircraft while on duty. RESULTS: One hundred and sixty-three pilots were included, with flying platforms ranging from fighter jets (n=54), combat helicopters (n=27), transport helicopters (n=52) and transport aircraft (n=30). These were compared with the results from 17 ATCs. A marked notch in the frequency range of 4-6 kHz was demonstrated in the mean audiograms of all platforms pilots, progressing with ageing. Hearing threshold shifts in relation to measurements at recruitment were first noted at the age of 30 years, particularly at 4 kHz (mean shift of 2.97 dB, p=0.001). There was no statistical association between flying variables and hearing thresholds adjusted for age by logistic regression analysis. CONCLUSIONS: The audiometric profile of IAF pilots has a pattern compatible with noise exposure, as reflected by characteristic noise notch. However, no flight variable was associated with deterioration of hearing thresholds, and no significant difference from non-flying controls (ATCs) was seen.

New onset diabetes after kidney transplantation is associated with increased mortality-A retrospective cohort study.

OBJECTIVE: Clinical outcomes in individuals with new onset diabetes after transplantation (NODAT) and the optimal treatment for this complication are poorly characterized. This study was intended to better define these issues. METHODS: Patients who underwent kidney transplantation and did not have diabetes prior to transplantation were included in the study. Clinical outcomes were compared between those who developed NODAT and those who did not. In those who developed NODAT, oral therapy was compared with insulin based therapy. RESULTS: A total of 266 kidney transplant recipients were included, of which 71 (27%) developed NODAT during the time of the follow-up. Using Cox multivariate analysis adjusted for age and gender, hazard ratio for overall mortality among patients with NODAT versus those without NODAT was 2.69 (95% CI 1.04-7.01). Among patients who developed NODAT, 29 patients (40%) were treated with an insulin-based regimen. At the end of follow-up, no difference was found in mean HbA1c, and therapy regimen was not associated with greater mortality. CONCLUSIONS: New onset diabetes in kidney transplanted patients is associated with increased mortality compared with kidney transplanted patients without NODAT.

Epigenetic pathway inhibitors represent potential drugs for treating pancreatic and bronchial neuroendocrine tumors.

Cancer is associated with alterations in epigenetic mechanisms such as histone modifications and methylation of DNA, and inhibitors targeting epigenetic mechanisms represent a novel class of anti-cancer drugs. Neuroendocrine tumors (NETs) of the pancreas (PNETs) and bronchus (BNETs), which may have 5-year survivals of <50% and as low as 5%, respectively, represent targets for such drugs, as >40% of PNETs and ~35% of BNETs have mutations of the multiple endocrine neoplasia type 1 (MEN1) gene, which encodes menin that modifies histones by interacting with histone methyltransferases. We assessed 9 inhibitors of epigenetic pathways, for their effects on proliferation, by CellTiter Blue assay, and apoptosis, by CaspaseGlo assay, using 1 PNET and 2 BNET cell lines. Two inhibitors, referred to as (+)-JQ1 (JQ1) and PFI-1, targeting the bromo and extra terminal (BET) protein family which bind acetylated histone residues, were most effective in decreasing proliferation (by 40-85%, P<0.001) and increasing apoptosis (by 2-3.6 fold, P<0.001) in all 3 NET cell lines. The anti-proliferative effects of JQ1 and PFI-1 remained present for at least 48 hours after removal of the compound. JQ1, but not PFI-1, had cell cycle effects, assessed by propidium iodide staining and flow cytometry, resulting in increased and decreased proportions of NET cells in G1, and S and G2 phases, respectively. RNA Sequencing analysis revealed that these JQ1 effects were associated with increased histone 2B expression, and likely mediated through altered activity of bromodomain-containing (Brd) proteins. Assessment of JQ1 in vivo, using a pancreatic beta cell-specific conditional Men1 knockout mouse model that develops PNETs, revealed that JQ1 significantly reduced proliferation (by ~50%, P<0.0005), assessed by bromodeoxyuridine incorporation, and increased apoptosis (by ~3 fold, P<0.0005), assessed by terminal deoxynucleotidyl transferase dUTP nick end labelling, of PNETs. Thus, our studies demonstrate that BET protein inhibitors may provide new treatments for NETs.

From pituitary adenoma to pituitary neuroendocrine tumor (PitNET): an International Pituitary Pathology Club proposal.

The classification of neoplasms of adenohypophysial cells is misleading because of the simplistic distinction between adenoma and carcinoma, based solely on metastatic spread and the poor reproducibility and predictive value of the definition of atypical adenomas based on the detection of mitoses or expression of Ki-67 or p53. In addition, the current classification of neoplasms of the anterior pituitary does not accurately reflect the clinical spectrum of behavior. Invasion and regrowth of proliferative lesions and persistence of hormone hypersecretion cause significant morbidity and mortality. We propose a new terminology, pituitary neuroendocrine tumor (PitNET), which is consistent with that used for other neuroendocrine neoplasms and which recognizes the highly variable impact of these tumors on patients.

Are Thyroid Hormone Values Obtained in Hospitalized Elderly Patients Reproducible? - A Cohort Study.

It is unclear whether TSH should be obtained in elderly hospitalized patients as several factors associated with hospitalization influence these levels, which may not truly represent the thyroid status of the individual. All patients≥65 years old hospitalized in a geriatric ward in the years 2012-2014 had TSH measured irrespective of the cause for hospitalization. All patients in whom TSH levels were performed in an ambulatory setting 2-12 months following hospitalization were identified and these TSH levels were correlated with levels recorded during hospitalization. Factors influencing TSH reproducibility were identified through review of patients' medical records. Of 562 patients hospitalized during the study period, 198 had repeat ambulatory TSH measurements during follow-up. The Katz Index of Independence was higher (9.43±2.98 vs. 8.43±3.67 p=0.002) and cerebrovascular disease was less prevalent (15.6 vs. 25.2% p=0.014) in those who had a repeat TSH measurement compared with those who did not, but other baseline characteristics and TSH levels on admission were similar. Ambulatory TSH values were significantly correlated with those obtained during hospitalization (correlation coefficient=0.677), irrespective of baseline systolic blood pressure, cause of hospitalization, or admission albumin levels. Mean TSH difference between in-hospital and ambulatory was 0.65±2.36 mIU/l and in more than 94% of cases TSH values differed by less than 2 mIU/l between the 2 measurements. In hospitalized patients≥65 years old, TSH levels are highly concordant with ambulatory values. TSH obtained during hospitalization may be used for making treatment decisions and has clinical utility in this population.

Blood pressure response to medical treatment in the emergency department - a retrospective cohort study.

OBJECTIVES: It is unclear whether blood pressure (BP) without target organ damage should be decreased in patients in the emergency department (ED). It is also uncertain whether any certain class of medications has an advantage over the other in this setting. This study addressed both these questions. METHODS: In this retrospective cohort study, all patients attending a tertiary care ED with elevated BP were evaluated. All patients with target organ damage as well as those with significant active co-morbidities, such as myocardial ischemia, were excluded. Baseline characteristics and response of BP to therapy were compared between those treated and untreated in the ED. In addition, BP response to therapy was compared between different classes of antihypertensive medications. RESULTS: Overall, 438 patients were included in the final analysis (62% female), of which 275 (63%) were treated in the ED. Antihypertensive medications were more commonly prescribed in the ED for those with higher systolic and diastolic BP, but other baseline characteristics were similar between the two groups. Only systolic BP significantly decreased in those treated with antihypertensive medications compared with those untreated. The most commonly used classes were angiotensin converting enzyme inhibitors (ACEis) and calcium channel blockers (CCBs). Use of either of these drug classes was not associated with a significant decrease in either systolic or diastolic BP compared with the use of other drug classes. CONCLUSIONS: Antihypertensive drug therapy is more commonly prescribed in the ED in individuals with both elevated systolic and diastolic BP, but leads to a significant decrease only in systolic BP. Use of either ACEis or CCBs is not associated with a significant decrease in either systolic or diastolic BP compared with other drug classes.

A thymic neuroendocrine tumour in a young female: a rare cause of relapsing and remitting Cushing's syndrome.

UNLABELLED: We present a case of a young female patient with a rare cause of relapsing and remitting Cushing's syndrome due to ectopic ACTH secretion from a thymic neuroendocrine tumour. A 34-year-old female presented with a constellation of symptoms of Cushing's syndrome, including facial swelling, muscle weakness and cognitive impairment. We use the terms 'relapsing and remitting' in this case report, given the unpredictable time course of symptoms, which led to a delay of 2 years before the correct diagnosis of hypercortisolaemia. Diagnostic workup confirmed ectopic ACTH secretion, and a thymic mass was seen on mediastinal imaging. The patient subsequently underwent thymectomy with complete resolution of her symptoms. Several case series have documented the association of Cushing's syndrome with thymic neuroendocrine tumours (NETs), although to our knowledge there are a few published cases of patients with relapsing and remitting symptoms. This case is also notable for the absence of features of the MEN-1 syndrome, along with the female gender of our patient and her history of non-smoking. LEARNING POINTS: Ectopic corticotrophin (ACTH) secretion should always be considered in the diagnostic workup of young patients with Cushing's syndromeThere is a small but growing body of literature describing the correlation between ectopic ACTH secretion and thymic neuroendocrine tumours (NETs)The possibility of a MEN-1 syndrome should be considered in all patients with thymic NETs, and we note the observational association with male gender and cigarette smoking in this cohortAn exception to these associations is the finding of relatively high incidence of thymic NETs among female non-smoking MEN-1 patients in the Japanese compared with Western populationsThe relapsing and remitting course of our patient's symptoms is noteworthy, given the paucity of this finding among other published cases.

Reversal of severe cognitive impairment following medical treatment of cystic invasive giant prolactinoma.

UNLABELLED: Giant prolactinomas are rare tumours of the pituitary, which typically exceed 40 mm in their largest dimension. Impairment of higher cognitive function has been noted post-operatively after transcranial surgery and as a long-term consequence of the radiotherapy treatment. However, there has been little that is reported on such disturbances in relation to the tumour per se, and to our knowledge, there has been none in terms of responsivity to dopamine agonist therapy and shrinkage in these tumours. We present a case of successful restoration of severely impaired cognitive functions achieved safely after significant adenoma involution with medical treatment alone. LEARNING POINTS: Giant prolactinomas can be present with profound cognitive defects.Dopamine agonists remain in the mainstay first-line treatment of giant prolactinomas.Mechanisms of the reversible cognitive impairment associated with giant prolactinoma treatment appear to be complex and remain open to further studies.Young patients with giant prolactinomas mandate genetic testing towards familial predisposition.

The management of pre-hypertension in primary care: Is it adequate?

BACKGROUND: Pre-hypertension (pHT) is frequently diagnosed in the primary care setting, but its management by primary care physicians (PCPs) is not well characterized. METHODS: All individuals aged 30-45 years who were insured by Clalit Health services in the Tel Aviv district and had their blood pressure (BP) measured from January 2006 to December 2010 were evaluated. Individuals were divided into three groups based on their initial BP value: optimal (< 120/80 mmHg), normal (systolic BP 120-129 or diastolic 80-84 mmHg) and borderline (130-139/85-89 mmHg). Groups were compared regarding clinical and laboratory follow-up performed by their PCP. RESULTS: Of the 20,214 individuals included in the study, 6576 (32.5%) had values in the pHT range. Of these, 2126 (32.3% of those with pHT) had BP values defined as "borderline" and 4450 (67.6% of those with pHT) had BP values defined as "normal". The number of follow-up visits by the PCP and repeat BP measurement were similar in those with "optimal" BP and pHT. A third and fourth BP measurement were recorded more frequently in those with pHT. In those with pHT, there were more recorded BP measurements than in those with borderline BP (3.35 ± 3 vs. 3.23 ± 2.6), but the time from the initial to the second measurement and a record of a third and fourth measurement were the same in the two groups. CONCLUSION: Identification of pHT does not lead to a significant change in follow-up by PCPs, irrespective of BP values in the pHT range.

[18F]FDG-PET/CT for the diagnosis of patients with fever of unknown origin.

BACKGROUND AND AIMS: The diagnosis of patients with fever of unknown origin (FUO) remains a challenging medical problem. We aimed to assess the diagnostic contribution of 18-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET)/computed tomography (CT) for the evaluation of FUO. METHODS: We performed a 4-year retrospective single-center study of all hospitalized patients that underwent FDG-PET/CT for evaluation of FUO. The final diagnosis of the febrile disease was based on clinical, microbiological, radiological and pathological data available at the final follow-up. Predictors for a contributory exam were sought. RESULTS: One hundred and twelve patients underwent FDG-PET/CT for the investigation of FUO in the years 2008-2012 and were included in the study. A final diagnosis was determined in 83 patients (74%) and included: infectious disease in 49 patients (43%), non-infectious inflammatory disease in 17 patients (16%), malignancies in 15 patients (14%), other diagnoses in 2 patients (1.7%), FUO resolved with no diagnosis and no evidence of disease during a 6-month follow-up in 23 patients (20%), and death with fever and with no diagnosis in 6 patients (5%). Seventy-four FDG-PET/CT studies (66%) were considered clinically helpful and contributory to diagnosis (46% positive contributory value and 20.5% contributory to exclusion of diagnosis). PET/CT had a sensitivity of 72.2%, a specificity of 57.5%, a positive predictive value (PPV) of 74.2% and a negative predictive value (NPV) of 53.5%. On multivariable analysis, significant predictors of a positive PET/CT contributory to diagnosis were a short duration of fever and male gender. CONCLUSIONS: PET/CT is an important diagnostic tool for patients with FUO.