Lower Limit Of Normal Research Articles

Impaired right ventricular strain is associated with worse prognosis in patients with liver cirrhosis

Abstract Introduction Cirrhotic cardiomyopathy is a complication of liver cirrhosis accounting for significant morbidity and associated with reduced patient survival. It is characterized by reduced afterload, increased cardiac output, and diastolic dysfunction. However, there are limited data regarding the prognostic significance of right ventricular (RV) mechanics. Novel echocardiographic techniques such as speckle tracking echocardiography can detect subclinical myocardial dysfunction early in the course of non-ischemic myocardiopathies. Purpose To investigate the prognostic role of RV free wall strain (RVFWS) in patients with liver cirrhosis. Methods We prospectively enrolled 70 patients with liver cirrhosis in stable clinical condition. Patients with coronary artery disease, valvular heart disease, ongoing alcohol consumption or poor acoustic window were excluded from the study. Transthoracic echocardiography was performed and RVFWS was calculated from RV focused 4-chamber views using a dedicated software. Since RVFWS was as expected negative in all patients, absolute values were used for all calculations. Clinical and laboratory examination was also performed in all patients and the Model for End-Stage Liver Disease (MELD) score a widely used tool for assessing liver disease severity was calculated. All-cause mortality at 24 months was the primary endpoint and was available in all patients. Results Mean RVFWS in the cohort was 27.4±6.3% and using a lower normal limit of 20%, reduced RVFWS was detected in six patients. According to the Spearman coefficient analysis, RVFWS was correlated with MELD (rho=0.274, p=0.023) indicating increased values in patients with more advanced liver disease. According to the univariate Cox-regression proportion hazard models RVFWS as a continuous variable was not significantly correlated with worse two year survival (HR: 1.01 (0.95-1.08, p=0.658). Interestingly, among conventional echocardiographic parameters basal RV diameter (p=0.004) and right atrial end-systolic area (p=0.008) were associated with increased risk for the primary endpoint. The association of the primary endpoint with other parameters of RV systolic function was also not statistically significant. The Multivatiate Cox Regression survival analysis, which incorporated age, sex, MELD, hemoglobin, systolic blood pressure and cardiac output, showed that among echocardiographic parameters for the evaluation of the RV, only RVFWS showed a tendency to be associated with worse survival (p=0.062). When patients were stratified into tertiles according to RVFWS values, those in the first tertile (with lower absolute RVFWS values) had significantly increased hazard for the primary endpoint (HR: 5.82, 2.18-15.8, P<0.001) (figure 1). Conclusions RVFWS values are within normal limits in most patients with liver cirrhosis. When adjusted for the severity of the liver disease, reduced RVFWS values are associated with worse prognosis in cirrhotics.

Similarities of metabolomic disturbances in prematurity-associated obstructive lung disease to chronic obstructive pulmonary disease

Prematurity-associated lung disease (PLD) is a long-term consequence of preterm-birth. Since the underlying mechanisms of PLD remain poorly characterised, we compared the urinary metabolome between recently described spirometry phenotypes of PLD. Preterm- and term-born children aged 7–12 years, from the Respiratory Health Outcomes in Neonates (RHiNO) cohort, underwent spirometry and urine collection. The urinary metabolome was analysed by gas chromatography time-of-flight mass spectrometry. Preterm-born children were classified into phenotypes of prematurity-associated obstructive lung disease (POLD, Forced expiratory volume in 1 s (FEV1) < lower limit of normal (LLN), FEV1/Forced Vital Capacity (FVC) < LLN), prematurity-associated preserved ratio impaired spirometry (pPRISm, FEV1 < LLN, FEV1/FVC ≥ LLN) and Preterm/Term controls (FEV1 ≥ LLN). Metabolite set enrichment analysis was used to link significantly altered metabolites between the groups with metabolic pathways. Univariable and multivariable linear regression models examined associations between early and current life factors and significantly altered metabolites of interest. Urine from 197 preterm- and 94 term-born children was analysed. 23 and 25 were classified into POLD and pPRISm groups respectively. Of 242 identified metabolites, 49 metabolites were significantly altered in the POLD group compared with Preterm controls. Decreased capric acid (log2 fold change − 0.23; p = 0.003), caprylic acid (− 0.18; 0.003) and ceratinic acid (− 0.64; 0.014) in the POLD group, when compared to preterm controls, were linked with reduced β-oxidation of very long chain fatty acids (p = 0.004). Reduced alanine (log2 fold change − 0.21; p = 0.046), glutamic acid (− 0.24; 0.023), and pyroglutamic acid (− 0.17; 0.035) were linked with decreased glutathione metabolism (p = 0.008). These metabolites remained significantly associated with POLD in multivariable models adjusting for early/current life factors. The pPRISm urinary metabolome was minimally changed when compared with preterm-born controls. When compared to term-born subjects, alterations in tryptophan metabolism were implicated (p = 0.01). The urinary metabolome in POLD showed significantly altered β-oxidation of fatty acids and glutathione metabolism, implying alterations in cellular metabolism and oxidative stress. Similar findings have been noted in adults with chronic obstructive pulmonary disease. Given the similarity of findings between the POLD group and those reported for COPD, the POLD group should be considered at future risk of developing COPD.

A-159 Re-evaluating Ferritin Cutoffs for the Diagnosis of Iron Deficiency and Iron Deficiency Anemia

Abstract Background Iron deficiency (ID) is the most common nutrient deficiency in the world and iron deficiency anemia (IDA) is estimated to affect 1.24 billion people. Serum ferritin is an iron storage protein commonly used as a biomarker for ID and IDA. The ferritin lower limit of normal (LLN) defined in many clinical laboratories is lower than evidence-based cutoffs and may not detect ID and IDA with adequate sensitivity, particularly when sex-based reference intervals (RIs) are used. This may be due in part to the use of asymptomatic, iron-depleted individuals for RI studies. Recent efforts have been made to increase the LLN for ferritin to at least 30 ng/mL and re-evaluate sex based RIs to improve diagnosis of ID and IDA. In this study, we aimed to investigate LLN ferritin cutoffs for ID and IDA in our patient population. Methods Patient data from June 2022-May 2023 were collected with approval from the Institutional Review Board (IRB), including age, sex, and values for ferritin, iron, transferrin saturation, and hemoglobin. Patients were classified as iron replete (IR), ID, or IDA based on measurements for iron, transferrin saturation, and hemoglobin. IR patients were defined as having iron and transferrin saturation values within current RIs, while those below the cutoff were grouped as ID. ID and IDA were further classified based on hemoglobin values. A range of ferritin concentrations between 1 and 100 ng/mL were used to calculate true and false positive rates (TPR and FPR) and diagnostic accuracy (DA). Receiver operator characteristic (ROC) curve and J index analysis were used to define optimal ferritin cutoffs for ID and IDA. Results Data from 26,455 patients (65% female) were used in this study. Conclusions These findings highlight the need to re-examine ferritin RIs in the context of ID/IDA, especially for those patients assigned female at birth.

Anthropometric and Nutritional status of Chronic Obstructive Pulmonary Disease presenting in Acute Exacerbation in Tertiary care Hospital in Eastern Nepal

Background: There is scarcity of data regarding the nutritional status of COPD patients presenting in exacerbation in our setup, thus this observational study was conducted. Methods: We performed an observational study of patients with acute exacerbation of COPD, who were admitted in the Department of Pulmonary, Critical care and Sleep Medicine in tertiary hospital in eastern Nepal from April 2023 to June 2023. Results: During the study period, a total of 154 patients of COPD with exacerbations were admitted in our department. The baseline anthropometric parameters, lab parameters as well as the malnutrition scores were determined. The mean BMI was 21.82 ± 3.92 kg/m2 and only 29% had BMI &lt; 18.5 kg/m2.The mean hemoglobin, mean cell volume, serum protein, serum albumin, serum calcium, phosphorus and vitamin D level were 12.43 ± 2.32 g/dL, 84.4 ± 9.41 fL, 6.42 ± 1.74 g/ dL, 3.32 ± 0.34 g/dL, 8.98 ± 0.63 mg/dL, 3.02 ± 0.42 mg/dL, 18.48 ± 8.22 pg/mL and 40%, 12%, 28%, 41%, 31%, 42% and 49% of these values were below the lower normal limit respectively. The nutritional status tool used NRS-2002, MUST and MNAS-F screened malnutrition in about 68%, 51% and 54% respectively. There shows a discrepancy between the evaluation of the malnutrition assessed by BMI with that of nutritional assessment score. Conclusion: COPD who present in exacerbations are malnourished, but use of sole BMI to rule out malnutrition in such group of patients can cause false negative result.

Lung function at 1-year follow-up in patients with persistent dyspnea after mild COVID-19 – comparisons with moderate and critical COVID-19

Aim: To assess lung function in patients with persistent dyspnea 1 year after mild coronavirus disease 2019 (COVID-19) and compare with those hospitalized with moderate or critical COVID-19. Methods: Adults with confirmed severe acute respiratory syndrome coronavirus-2 infection with mild COVID-19 and persistent dyspnea (n = 18) or with moderate (n = 34) or critical COVID-19 (n = 19) were followed up 11–13 months after initial infection. Inclusion criteria were age &lt; 65 years, no smoking history, and no preexisting respiratory diseases. Sociodemographic and clinical data were collected, and patients underwent spirometry and measurement of diffusing capacity for carbon monoxide (DLCO). Results: The non-hospitalized patients were significantly younger and more often female compared with those in the moderate and critical groups (P = 0.002 and P &lt; 0.001, respectively). No significant differences in comorbidities or body mass index (BMI) were noted between severity groups. An obstructive spirometry pattern (ratio of forced expiratory volume during the first exhalation second to forced vital capacity under the lower limit of normal (LLN)) was found in 5.6, 5.9, and 5.3% of patients in the mild, moderate, and critical groups, respectively (P = 0.995). Abnormal DLCO (&lt; LLN) rates were seen in 5.6, 16.7, and 47.4% in the mild, moderate, and critical groups, respectively (P = 0.018). DLCO, expressed as a z-score, was significantly lower in the critical group compared with the mild group after adjustment for age, sex, and BMI. Conclusion: Only a few subjects with mild COVID-19 and persistent dyspnea had abnormal lung function 1 year after initial infection, assessed based on spirometry and DLCO measurements. An obstructive spirometry pattern at 1-year follow-up was uncommon even in patients with moderate or critical COVID-19. Impaired DLCO was more common in patients with critical COVID-19.

Prevalence and etiotypes of persistent airflow obstruction in the general population across the lifetime

Background and objectivesDifferent factors (etiotypes) can lead to persistent airflow obstruction (PAO) across the lifetime, including genetic factors, abnormal lung development, cigarette smoking, traffic pollution exposure, respiratory infections and asthma. Here we explore the prevalence of PAO and associated etiotypes in the general population in different age bins. MethodsWe studied 664 individuals with PAO (FEV1/FVC post bronchodilation (post-BD) below the lower limit of normal (LLN)) and 11,522 with normal lung function (FEV1/FVC, FEV1 and FVC ≥ LLN and ≤ upper limit of normal (ULN) post-BD) included in the LEAD Study (NCT01727518), a general population cohort in Vienna (Austria). For analysis, participants were stratified in three age bins (<25, 25-<50 and ≥ 50 years of age). ResultsPAO occurred in 3.8 % in females and 5.6 % in males of the cohort, and it increased with age. Most participants with PAO (57.5 %) reported respiratory symptoms, indicating a high burden of disease. PAO was associated with male sex (25-<50 years), ever smoking (>50 years), increased number of pack years (25-<50 years, >50 years), not being breastfed (<25 years) and ever diagnosis of asthma (in all age bins). Etiotypes varied by age bins with cigarette smoking being the most prevalent one, often in combination with traffic pollution exposure. ConclusionIn the general population PAO occurs in about 5 % of participants with a higher prevalence in older individuals. Etiotypes and associated factors for PAO accumulate with age.

Partial rescue of the full-field electroretinogram in patients with RPE65-related retinal dystrophy following gene augmentation therapy with voretigene neparvovec-rzyl.

To present a series of patients with RPE65-related retinal dystrophy showing a partial rescue of the full-field electroretinogram (ERG) following gene replacement therapy with voretigene neparovec-rzyl (Luxturna®). This retrospective chart review examined 17 patients treated with voretigene neparovec-rzyl (VN) at the Casey Eye Institute (2018-2022). The last pre-operative ERG and all available post-operative ERGs were analyzed to identify subjects with functional rescue. Measurements of amplitudes and implicit times were compared to data from age-matched controls and the attenuation relative to the lower limit of normal (LLN) was calculated. For comparison with other functional exams, the last pre-operative and all post-treatment best-corrected visual acuity (BCVA) data, visual field (VF) tests and full-field threshold stimulus tests (FST) were also described. Of patients who underwent ERGs, most had unrecordable ERGs that did not change after treatment. However, we identified three patients, treated bilaterally, who demonstrated partial rescue of the full-field ERG in both eyes which was sustained during the course of the study. This is the largest series of patients treated with VN showing a partial rescue of the ERG. This is also the first report of bilateral ERG rescue, as well as the first description of ERG recovery occurring in non-pediatric subjects. Full-field ERG could be used in combination with other psychophysical tests and imaging modalities to detect and deepen our understanding of the response to this gene therapy approach.

Central Venous Oxygen Saturation in Children With Cancer.

Central venous saturation (ScvO2) can guide resuscitation of children with septic shock. The normal range of ScvO2 is typically considered as 0.70-0.80, but has not been established in children with cancer. Children with cancer are particularly prone to develop sepsis due to their immunosuppressive therapy, and usually have a permanent central venous catheter, making ScvO2 readily available. We aimed to investigate normal values of ScvO2 in clinically stable children with cancer, and the association between ScvO2, hemoglobin, and lactate. We conducted a prospective clinical study at the outpatient clinic of a tertiary pediatric hematology/oncology unit. Blood samples were collected from stable children aged 0-17.9 years who were treated for cancer between January 1 and November 30, 2019, during their routine outpatient clinic visits. A total of 183 blood samples were collected from 68 patients (24 girls and 44 boys). The predicted mean level of ScvO2 with a 95% confidence interval was 0.67 (0.56-0.78). The ScvO2 value was below the expected lower normal limit of 0.70 in 126 (69%) of the samples and in 48 patients (71%) at least once. ScvO2 was significantly associated with hemoglobin (β1 = 0.012 per g/L hemoglobin, P < 0.001), but not with age, sex, underlying diagnosis, or lactate. The study revealed that a substantial portion of clinically stable childhood cancer patients exhibited ScvO2 levels below the typical reference value of 0.70, suggesting that these children may have inherently lower baseline ScvO2 levels. This should be kept in mind when evaluating children with cancer for septic shock, emphasizing the importance of tailored assessments in this population. Further understanding of baseline ScvO2 abnormalities may be helpful if ScvO2 is used to guide resuscitation.

Risk Factors, Morbidity, and Mortality in Association With Preserved Ratio Impaired Spirometry and Restrictive Spirometric Pattern: Clinical Relevance of Preserved Ratio Impaired Spirometry and Restrictive Spirometric Pattern

BackgroundPreserved Ratio Impaired Spirometry (PRISm) and Restrictive Spirometric Pattern (RSP) are often considered interchangeable in identifying restrictive impairment in spirometry. Research QuestionDo PRISm and RSP have different individual associations with risk factors, morbidity, and mortality? Study Design and MethodsIn a cross-sectional and longitudinal study, including 26,091 30–46-year-old Norwegian general population men, we explored the association of PRISm and RSP with smoking habits, BMI, education, respiratory symptoms, self-reported cardiopulmonary disease, and mortality after 26 years of follow-up. PRISm was defined as FEV1/FVC ≥ lower limit of normal (LLN) & FEV1<LLN, RSP as FEV1/FVC≥LLN & FVC<LLN. We compared the associations of PRISm and RSP to airflow obstruction and normal spirometry, both as mutually (PRISm-alone, RSP-alone) and non-mutually exclusive (PRISm, RSP) categories, adjusting for age, BMI, smoking, education. We also conducted sensitivity analyses using GOLD criteria to define spirometric abnormalities. ResultsThe prevalence of the mutually exclusive spirometric patterns was: normal 82.4%, obstruction 11.0%, PRISm-alone 1.4%, RSP-alone 1.7%, PRISm+RSP 3.5%. PRISm-alone subjects were frequently obese (11.2%), current or former smokers, commonly reporting cough, phlegm, wheeze, asthma, and bronchitis. RSP-alone subjects were both obese (14.6%) and underweight (2.9%), with increased breathlessness, but similar smoking habits to subjects with normal spirometry. The prevalence of heart disease was 4.6% in PRISm-alone, 2.7% in RSP-alone and 1.6% in obstruction. With normal spirometry as a reference, RSP-alone had increased all-cause (HR 1.57 (1.21–2.04 95%CI), cardiovascular (1.48 (0.88–2.48)), diabetes (6.43 (1.88–21.97)), and cancer (excl. lung) mortality (1.51 (0.95–2.42)). PRISm-alone had increased respiratory disease mortality (HR 4.00 (1.22–13.16 95%CI)). Subjects with PRISm+RSP had intermediate characteristics and the worst prognosis. Findings were overall confirmed with non-mutually exclusive categories and GOLD criteria. InterpretationPRISm and RSP are spirometric patterns with distinct risk factors, morbidity and mortality, which should be differentiated in future studies.

Bedside assessment of sarcopenia in hospitalized patients with liver cirrhosis: Magnitude and clinical implications.

Sarcopenia is associated with many adverse outcomes in patients with cirrhosis. The tools currently in use for assessing sarcopenia have numerous flaws. We evaluated the utility of portable ultrasonography and a dynamometer for the bedside assessment of sarcopenia and its implications in hospitalized cirrhosis patients. A dynamometer was used to test the hand-grip strength (HGS) and ultrasound was used to measure the thickness of the forearm and quadriceps muscles. HGS value < 27kg for men and < 16kg for women was taken as significant according to the European Working Group on Sarcopenia in Older People (EWGSOP2) criteria. The lower normal limit of muscle mass (5th percentile) was determined on 100 matched healthy controls. According to the EWGSOP2 criteria and HGS values, the prevalence of sarcopenia and probable sarcopenia among 300 cirrhosis patients were 56% and 62.3%, respectively. HGS alone identified sarcopenia in 88.9% of patients, while overestimated it in 6.3% of cases. The prevalence rate of sarcopenic obesity was 11%. Compared to patients without sarcopenia, sarcopenic patients had more complications of cirrhosis such as ascites, variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, sepsis, hepatorenal syndrome and refractory ascites. In-hospital (p = 0.037), three-month (p < 0.001), and six-month (p < 0.001) mortality rates were all higher among sarcopenic patients. On cox regression survival analysis, overall six-month mortality was significantly higher in sarcopenic patients compared to patients without sarcopenia (hazard ratio, 6.37; 95% confidence interval, 3.15-12.8, p < 0.001). Bedside assessment of sarcopenia using a portable ultrasound machine and a dynamometer detects liver cirrhosis patients with high risk of complications and mortality.

The challenges of recruiting never-smokers with chronic obstructive pulmonary disease from the large population-based Swedish CArdiopulmonary bioImage study (SCAPIS) cohort

ABSTRACT Background A substantial proportion of individuals with COPD have never smoked, and it is implied to be more common than previously anticipated but poorly studied. Aim To describe the process of recruitment of never-smokers with COPD from a population-based cohort (n = 30 154). Methods We recruited never-smokers with COPD, aged 50–75 years, from six University Hospitals, based on: 1) post broncho-dilator forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) < 0.70 and 2) FEV1 50–100% of predicted value and 3) being never-smokers (self-reported). In total 862 SCAPIS participants were identified, of which 652 were reachable and agreed to a first screening by telephone. Altogether 128 (20%) were excluded due to previous smoking or declined participation. We also applied a lower limit of normal (LLN) of FEV1/FVC (z-score<-1.64) according to the Global Lung Initiative to ensure a stricter definition of airflow obstruction. Results Data on respiratory symptoms, health status, and medical history were collected from 492 individuals, since 32 were excluded at a second data review (declined or previous smoking), prior to the first visit. Due to not matching the required lung function criteria at a second spirometry, an additional 334 (68%) were excluded. These exclusions were by reason of: FEV1/FVC ≥0.7 (49%), FEV1 > 100% of predicted (26%) or z-score ≥ −1,64 (24%). Finally, 154 never-smokers with COPD were included: 56 (36%) women, (mean) age 60 years, FEV1 84% of predicted, FEV1/FVC: 0.6, z-score: −2.2, Oxygen saturation: 97% and BMI: 26.8 kg/m2. Conclusions The challenges of a recruitment process of never-smokers with COPD were shown, including the importance of correct spirometry testing and strict inclusion criteria. Our findings highlight the importance of repeated spirometry assessments for improved accuracy in diagnosing COPD.

Symptoms of COPD in the absence of airflow obstruction are more indicative of pre-COPD than overdiagnosis.

Dysfunction of the small airways is a precursor of COPD but is not detectable on standard spirometric testing until significant destruction has occurred. A proportion of COPD patients have a forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <0.7 which is greater than the lower limit of normal (LLN), when adjusted for their age and sex. It is not understood whether this group of patients, known as "discordant COPD", are representative of "early COPD" or overdiagnosis. We sought to characterise discordant COPD (disCOPD) using radiology, lung function, serum biomarkers, activity monitoring and quality-of-life scores, comparing with COPD patients with an FEV1/FVC <0.7 and <LLN and healthy, age-matched controls. Six out of eight serum biomarkers were significantly different in the disCOPD group versus healthy controls, as were the scores of all four quality-of-life questionnaires. Activity monitoring revealed similar levels of sedentary time between the disCOPD group and concordant COPD (conCOPD). Computed tomography analysis showed less involvement of small airway dysfunction and emphysema in the disCOPD group versus conCOPD. Collectively, our findings support the hypothesis that disCOPD is a clinically relevant phenomenon that represents a pre-COPD state. Identification of such patients is important for early intervention and management before progression to fully established COPD.

Pulmonary Function Tests: Easy Interpretation in Three Steps.

Pulmonary function tests (PFTs) are pivotal in diagnosing and managing a broad spectrum of respiratory disorders. These tests provide critical insights into lung health, guiding diagnoses, assessing disease severity, and shaping patient management strategies. This review addresses the complexities and nuances inherent in interpreting PFT data, particularly in light of recent updates from the European Respiratory Society (ERS) and American Thoracic Society (ATS). These updates have refined interpretive strategies, moving away from definitive diagnostic uses of spirometry to a more probabilistic approach that better accounts for individual variability through the use of Z-scores and lower limits of normal (LLNs). Significantly, this narrative review delves into the philosophical shift in spirometry interpretation, highlighting the transition from direct clinical diagnostics to a more nuanced evaluation geared towards determining the likelihood of disease. It critiques the reliance on fixed ratios and emphasizes the need for reference values that consider demographic variables such as age, sex, height, and ethnicity, in line with the latest Global Lung Function Initiative (GLI) equations. Despite these advances, challenges remain in ensuring uniformity across different predictive models and reference equations, which can affect the accuracy and consistency of interpretations. This paper proposes a streamlined three-step framework for interpreting PFTs, aiming to unify and simplify the process to enhance clarity and reliability across various medical specialties. This approach not only aids in accurate patient assessments but also mitigates the potential for misdiagnosis and ensures more effective patient management. By synthesizing contemporary guidelines and integrating robust physiological principles, this review fosters a standardized yet flexible approach to PFT interpretation that is both scientifically sound and practically feasible.

Development of normal reference intervals for renal function in pregnancy: a secondary analysis of clinical trial data

Background Due to its potential nephrotoxicity, screening for pre-existing renal function disorders has become a routine clinical assessment for initiating Tenofovir diphosphate fumarate (TDF)-containing antiretroviral treatment (ART) or pre-exposure prophylaxis (PrEP) in pregnant and non-pregnant adults. We aimed to establish reference values for commonly used markers of renal function in healthy pregnant women of African origin. Methods Pregnant women ≥18 years, not living with HIV, and at 14–28 weeks gestation were enrolled in a PrEP clinical trial in Durban, South Africa between September 2017 and December 2019. Women were monitored 4-weekly during pregnancy until six months postpartum. We measured maternal weight and serum creatinine (sCr) at each visit and calculated creatinine clearance (CrCl) rates using the Cockcroft–Gault (CG) and Modification of Diet in Renal Disease (MDRD) formulae. Reference ranges for sCr and CrCl by CG and MDRD calculations were derived from the mean ± 2SD of values for pregnancy and postdelivery. Results Between 14-–and 40 weeks gestation, 249 African women not exposed to TDF-PrEP contributed a total of 1193 renal function values. Postdelivery, 207 of these women contributed to 800 renal function values. The normal reference range for sCr was 30–57 and 32–60 umol/l in the 2nd and 3rd trimesters of pregnancy. Normal reference ranges for CrCl using the MDRD calculation were 129–282 and 119–267 ml/min/1.73m2 for the 2nd and 3rd trimesters, respectively. Using the CG method of calculation, normal reference ranges for CrCl were 120—304 and 123–309 ml/min/1.73m2 for the 2nd and 3rd trimesters respectively. In comparison, the normal reference range for sCr, CrCl by MDRD and CG calculations postpartum was 40–77 umol/l, 92–201, and 90–238 ml/min/1.73m2, respectively. Conclusions In African women, the Upper Limit of Normal (ULN) for sCr in pregnancy is approximately 20% lower than 6 months postnatally. Inversely, the Lower Limit of Normal (LLN) for CrCl using either MDRD or CG equation is approximately 35% higher than 6 months postnatally. We provide normal reference ranges for sCr and CrCl for both methods of calculation and appropriate for the 2nd and 3rd trimesters of pregnancy in African women.

Normalization of Hemoglobin, Lactate Dehydrogenase, and Fatigue in Patients with Paroxysmal Nocturnal Hemoglobinuria Treated with Pegcetacoplan.

We determined normalization rates for hemoglobin, lactate dehydrogenase (LDH), and fatigue in patients with paroxysmal nocturnal hemoglobinuria (PNH) treated with pegcetacoplan (PEG) in the PEGASUS (NCT03500549) and PRINCE (NCT04085601) phase III trials. Enrolled patients had PNH and hemoglobin <10.5 g/dL despite ≥3 months of eculizumab (ECU) [PEGASUS], or were complement component 5 (C5) inhibitor-naive, receiving supportive care only, with hemoglobin less than the lower limits of normal (LLN) [PRINCE]. Hematologic and fatigue normalization endpoints were hemoglobin greater than or equal to the LLN (females: 12 g/dL; males: 13.6 g/dL) in the absence of transfusion; LDH ≤226U/L in the absence of transfusion; and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue ≥43.6, the general population norm. Safety was assessed by investigators using standardized terms and definitions for seriousness and severity. Hemoglobin normalization occurred in 34.1% (14/41) of PEG-treated patients at Week 16 (randomized controlled period) in PEGASUS (vs. 0% [0/39] of ECU-treated patients) and in 45.7% (16/35) of PEG-treated patients at Week 26 in PRINCE (vs. 0% [0/18] of supportive care-treated patients). At Week 48 (open-label period) in PEGASUS, 24.4% of PEG-treated patients (PEG-to-PEG) and 30.8% of patients treated with ECU through Week 16 who switched to PEG through Week 48 (ECU-to-PEG) had hemoglobin normalization. Rates of LDH normalization in PEGASUS were 70.7% (PEG-treated patients) and 15.4% (ECU-treated patients) at Week 16, and 56.1% (PEG-to-PEG) and 51.3% (ECU-to-PEG) at Week 48. In PRINCE, 67.5% of PEG-treated patients at Week 26 had normalized LDH concentrations. Rates of FACIT-Fatigue score normalization in PEGASUS were 48.8% and 10.3% in PEG- and ECU-treated patients, respectively, at Week 16, and 34.1% and 51.3% in PEG-to-PEG- and ECU-to-PEG-treated patients, respectively, at Week 48. In PRINCE, 68.6% of PEG-treated patients and 11.1% of supportive care patients had FACIT-Fatigue score normalization at Week 26. PEG was safe and well tolerated. Injection site reactions, mostly mild, were the most common adverse event of special interest in PEG-treated patients in the PEGASUS randomized controlled period (36.6%) and in PRINCE (30.4%). PEG is superior to ECU and supportive care in hemoglobin, LDH, and FACIT-Fatigue score normalization for patients with PNH and persistent anemia despite ≥3 months of treatment with ECU, and in C5 inhibitor-naive patients. The PEGASUS trial (NCT03500549) was registered on 18 August 2018, and the PRINCE trial (NCT04085601) was registered on 11 September 2019.

The status and influencing factors of lung ventilation function in employees exposed to dust in enterprises of the XPCC, China.

Occupational health is closely related to harmful factors in the workplace. Dust is the primary contributing factor causing impaired lung ventilation function among employees with dust exposure, and their lung ventilation function may also be influenced by other factors. We aimed at assessing the status and influencing factors of lung ventilation function among employees exposed to dust in the enterprises of the Eighth Division located in the Xinjiang Production and Construction Corps (XPCC), China. Employees exposed to dust in enterprises of the Eighth Division located in the XPCC in 2023 were selected as the subjects of this cross-sectional study. Their lung ventilation function indicators were extracted from health examination records, and an on-site electronic questionnaire survey was conducted among them. Binary logistic regression analyses were conducted to evaluate the factors influencing lung ventilation function. According to the fixed value criteria, the abnormal rates of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and FEV1/FVC were 31.6, 1.4, and 0.4%, respectively. The lower limit of normal (LLN) criteria could overestimate the rate of abnormal lung ventilation function. Several factors were related to impaired lung ventilation function, including gender, age, education level, marital status, body mass index (BMI), smoking status, physical activity, the type of dust, industry, enterprise scale, occupation, length of service, working shift, monthly income, and respiratory protection. A relatively low abnormal rate of lung ventilation function was observed among employees exposed to dust in enterprises of the Eighth Division, XPCC, and their lung ventilation function was associated with various factors. Effective measures should be taken urgently to reduce the effects of adverse factors on lung ventilation function, thereby further protecting the health of the occupational population.

Outcome-based Definition of the Lower Limit of Normal in Spirometry: A Study of 26,000 Young Adult Men.

Rationale: The definition of the lower limit of normal (LLN) of spirometric variables is not well established. Objectives: To investigate the relationship between spirometric abnormalities defined with different thresholds of the LLN and clinical outcomes and to explore the possibility of using different LLN thresholds according to the pretest probability of disease. Methods: We studied the associations between prebronchodilator spirometric abnormalities (forced expiratory volume in the first second [FEV1] < LLN, forced vital capacity [FVC] < LLN, airflow obstruction, spirometric restriction) defined with different thresholds of the LLN (10th, 5th, 2.5th, 1st percentile) and multiple outcomes (prevalence of spirometric abnormalities, respiratory symptoms, all-cause and respiratory mortality) in 26,091 30- to 46-year-old men who participated in a general population survey in Norway in 1988-1990 and were followed for 26 years. Analyses were performed with both local and Global Lung Function Initiative (GLI)-2012 reference equations, stratified by pretest risk (presence or absence of respiratory symptoms), and adjusted for age, body mass index, smoking, and education. Results: In the total population, the prevalence of airflow obstruction was 11.6% with GLI-LLN10, 11.0% with Local-LLN5, 6.1% with GLI-LLN5, 7.6% with Local-LLN2.5, and 3.5% with GLI-LLN2.5. The prevalence of spirometric restriction was 5.9% with GLI-LLN10, 5.2% with Local-LLN5, and 2.8% with GLI-LLN5. Increasingly lower thresholds of the LLN were associated with increasingly higher odds of respiratory symptoms and hazard of mortality for all spirometric abnormalities with both reference equations. Spirometric abnormalities defined with Local-LLN2.5 in asymptomatic subjects were associated with lower hazard of all-cause mortality (hazard ratio [HR], 1.50; 95% confidence interval [CI], 1.15-1.95 for FEV1 < LLN) than those defined with Local-LLN5 in the general population (HR, 1.67; 95% CI, 1.50-1.87 for FEV1 < LLN) and symptomatic subjects (HR, 1.67; 95% CI, 1.46-1.91 for FEV1 < LLN). Overall, the prevalence of spirometric abnormalities and associations with outcomes obtained with Local-LLN5 were comparable to those obtained with GLI-LLN10 and those obtained with Local-LLN2.5 to GLI-LLN5. Conclusions: There is a relationship between statistically based thresholds of the LLN of spirometric variables and clinical outcomes. Different thresholds of the LLN may be used in different risk subgroups of subjects, but the choice of the threshold needs to be evaluated together with the choice of reference equations.

Application of the ERS/ATS Spirometry Standards and Race-Neutral Equations in the COPDGene Study.

The European Respiratory Society (ERS) and the American Thoracic Society (ATS) recommend using z-scores, and the ATS has recommended using Global Lung Initiative (GLI)- "Global" race-neutral reference equations for spirometry interpretation. However, these recommendations have been variably implemented and the impact has not been widely assessed, both in clinical and research settings. We evaluated the ERS/ATS airflow obstruction severity classification. In the COPDGene Study (n = 10,108), airflow obstruction has been defined as a forced expiratory volume in one second to forced vital capacity (FEV1/FVC) ratio <0.70, with spirometry severity graded from class 1 to 4 based on race-specific percent predicted (pp) FEV1 cut-points as recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). We compared the GOLD approach, using NHANES III race-specific equations, to the application of GLI-Global equations using the ERS/ATS definition of airflow obstruction as FEV1/FVC ratio < lower limit of normal (LLN) and z-FEV1 cut-points of -1.645, -2.5, and -4 ("zGLI Global"). We tested the four-tier severity scheme for association with COPD outcomes. The lowest agreement between ERS/ATS with zGLI Global and the GOLD classification was observed in individuals with milder disease (56.9% and 42.5% in GOLD 1 and 2) and race was a major determinant of redistribution. After adjustment for relevant covariates, zGLI Global distinguished all-cause mortality risk between normal spirometry and the first grade of COPD (Hazard Ratio 1.23, 95% CI 1.04-1.44, p=0.014), and showed a linear increase in exacerbation rates with increasing disease severity, in comparison to GOLD. The zGLI Global severity classification outperformed GOLD in the discrimination of survival, exacerbations, and imaging characteristics.

Lung outcomes and related risk factors in patients after SARS-CoV-2 infection: a hospitalised single-centre cohort from Johannesburg, South Africa

Sequelae post-SARS-CoV-2 infection, including lung and functional impairment, pose a significant challenge post-recovery. We explored the burden and risk factors for post-COVID-19 sequelae in an African population with prevalent comorbidities including tuberculosis (TB) and HIV. We conducted an observational cohort study on hospitalised adults with confirmed SARS-CoV-2 infection from 20 March to 06 October 2021at Chris Hani Baragwanath Academic Hospital, South Africa. We collected data on comorbidities, and COVID-19 severity using the World Health Organization (WHO) clinical progression scale. Prospectively, we followed up all participants within 40-days post-discharge to assess body mass index (BMI), COVID-19 symptoms and quality of life using St George's Respiratory Questionnaire (SGRQ), 6-min walking-test (6MWT), and spirometry. A subsequent in-depth visit assessed plethysmography, diffusing capacity for the lung for carbon monoxide (DLCO), and high-resolution chest-CT. We followed up 111 participants, where 65.8% were female, median age 50.5 years, and predominantly black-African (92.8%). Relevant comorbidities included TB disease (18.9%) and HIV infection (36%). SGRQ total scores were elevated in 78.9%, median 6MWT distance was reduced at 300m (IQR 210-400), and nearly half (49.5%) exhibited spirometry findings below the lower limit of normal (LLN). In-depth pulmonary assessment for 61 participants revealed abnormalities in total lung capacity (31.6%<80% predicted), DLCO (53.4%<80% predicted), and chest-CT (86.7% abnormal). Significant risk factors for individual abnormal outcomes, adjusted for age and sex, were TB disease, HIV with CD4 <200cells/mm3, BMI <18.5kg/m2 and >35kg/m2, and initial COVID-19 severity. This study demonstrates substantial lung and functional morbidity within the first weeks post-COVID-19, particularly in individuals with pre-existing comorbidities including TB, HIV, and low or high BMI. Chest-CT and DLCO show best early potential at reflecting COVID-19-related pathologies. The Bavarian State Ministry of Science and Arts.

The Role of Hypogonadism in the Body Composition of Obese Men in the Preoperative Period of Bariatric Surgery

ObjectiveTo describe clinical characteristics, hormonal profile and body composition of obese men in preoperative of bariatric surgery. MethodsCross-sectional, population-based study. Patients evaluated from June 2019 to December 2021 in 2 obesity referral centers. Patients underwent clinical evaluation, androgen deficiency screening using Androgen Deficiency in the Aging Male questionnaire, hormonal profile and body composition assessment through body mass index (BMI), body fat percentage (FM-%) and mass (FM-kg) measured by electrical bioimpedance and dual energy x-ray absorptiometry. To characterize hypogonadism, 2 cut-off points were considered: TT <264 ng/dL and TT <164 ng/dL. ResultsThirty patients were included, mean age 35.6 ± 8.8 years, mean weight 129.4 ± 14.0 kg and mean BMI 42.3 ± 4.7 kg/m2. Dyslipidemia was the most prevalent comorbidity. Considering TT <264 ng/dL, 22 patients (73%) had hypogonadism. The mean TT in hypogonadal men was 198.9 + 68.7 ng/dL and in eugonadal men 357.0 + 59.5 ng/dl (P < .001). Using TT <164 ng/dL, 7 patients (23%) had hypogonadism. The mean TT in hypogonadal patients was 116.6 + 28.9 ng/dL and in eugonadal patients 279.0 + 75.0 ng/dL (P < .001). In Androgen Deficiency in the Aging Male questionnaire, 93.3% had positive screening, with no significant difference between groups. There was no statistically significant difference in body composition between groups when using TT <264 ng/dL as the hypogonadism cutoff. Considering hypogonadism TT <164 ng/dL, hypogonadal patients had significantly higher values of weight (139.0 × 126.5 kg P = .036), BMI (46.1 × 41.2 kg/m2P = .014), FM-% (48.0 × 42.8% P = .010) and FM-kg (66.3 × 53.9 kg P = .007) than eugonadal patients. ConclusionHypogonadism was identified in at least 23% of patients. Considering TT below the lower limit of normality for characterization of hypogonadism, we identified a significant worsening in body composition parameters.