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Aim: Growth reference values about mid‐upper arm circumference (MUAC) are vital for assessing children's nutritional status. However, Pakistan lacks these reference values and growth charts. This study aims to develop these for children aged 6–60 months and compare them with global standards. Methods: The data were acquired from the 2018 National Nutrition Survey of Pakistan, which was conducted by the United Nations Children's Fund (UNICEF) during 2018–2019. The final study cohort comprised 57 285 children, with 51% being boys. Percentile values and charts for MUAC‐for‐age were developed using generalised additive models for location, scale and shape with the Box–Cox power exponential distribution. Results: The mean MUAC was 14.21 cm (±2.07 cm) and 14.13 cm (±2.12 cm) for the boys and girls, respectively. At 60 months of age, the P3 and P97 percentiles for girls were slightly higher than those for boys. The median percentiles of Pakistani children were smaller than the World Health Organisation 2007 standards and with international references. Conclusion: We observed disparities in MUAC‐for‐age growth references among Pakistani children compared to global standards, highlighting regional, age and gender variations. This underscores the need for developing countries like Pakistan to establish their growth references. [ABSTRACT FROM AUTHOR]

Background: Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) may affect the male reproductive system as it uses angiotensin‐converting enzyme (ACE)2, which is expressed in testicular tissue, as an entry point into the cell. Few studies have evaluated the long‐term effects of mild coronavirus disease 2019 (COVID‐19) on testicular function, and insulin‐like factor 3 (INSL3) levels have not previously been assessed during acute SARS‐CoV‐2 infection. Objectives: The aim of the study was to assess the impact of acute SARS‐CoV‐2 infection on testicular function including INSL3 and the presence of SARS‐CoV‐2 RNA in semen in non‐hospitalised men with mild COVID‐19. Materials and methods: This longitudinal study included 36 non‐hospitalised SARS‐CoV‐2‐positive men (median age 29 years). Inclusion was within seven days following a positive SARS‐CoV‐2 reverse‐transcription polymerase chain reaction test. Reproductive hormone levels, semen parameters, and the presence of SARS‐CoV‐2 RNA in oropharyngeal and semen samples were assessed during acute SARS‐CoV‐2 infection (baseline) and at three‐ and six‐month follow‐up. Wilcoxon matched‐pair signed‐rank (two samples) test was used to assess time‐related alterations in reproductive hormone levels and semen parameters. Results: Lower plasma testosterone (T) (total and calculated free (c‐fT)) and higher luteinising hormone (LH) concentrations were observed during acute SARS‐CoV‐2 infection (baseline) compared to three‐ and six‐month follow‐up. Consequently, ratios of c‐fT/LH were lower at baseline compared to three‐ and six‐month follow‐up (p < 0.001 and p = 0.003, respectively). Concomitantly, lower INSL3 concentrations were observed at baseline compared to three‐month follow‐up (p = 0.01). The total number of motile spermatozoa was also lower at baseline compared to six‐month follow‐up (p = 0.02). The alterations were detected irrespective of whether the men had experienced SARS‐CoV‐2‐related fever episodes or not. No SARS‐CoV‐2 RNA was detected in semen at any time point. Discussion and conclusion: This study showed a reduction in testicular function, which was for the first time confirmed by INSL3, in men mildly affected by SARS‐CoV‐2 infection. The risk of transmission of SARS‐CoV‐2 RNA via semen seems to be low. Febrile episodes may impact testicular function, but a direct effect of SARS‐CoV‐2 cannot be excluded. [ABSTRACT FROM AUTHOR]

Objective: To evaluate whether optimized and standardized diagnostic procedures would improve detection of germ cell neoplasia in situ (GCNIS) in the contralateral testis of patients with testicular germ cell tumour (TGCT) and decrease the rate of metachronous tumours, which in a nationwide Danish study was estimated to be 1.9%. Patients and Methods: This was a retrospective analysis of outcomes in 655 patients with TGCT who underwent contralateral biopsies (1996–2007) compared with those in 459 non‐biopsied TGCT controls (1984–1988). The biopsies were performed using a standardized procedure with immunohistochemical GCNIS markers and assessed by experienced evaluators. Initial histopathology reports were reviewed, and pathology and survival data were retrieved from national Danish registers. In 604/608 patients diagnosed as GCNIS‐negative (four were lost to follow‐up), the cumulative incidence of metachronous TGCT was estimated in a competing risk setting using the Grey method. All cases of metachronous TGCT were re‐examined using immunohistochemistry. Results: Germ cell neoplasia in situ was found in 47/655 biopsied patients (7.2%, 95% confidence interval [CI] 5.4–9.5%). During the follow‐up period (median 17.3 years) five of the 604 GCNIS‐negative patients developed a TGCT. In 1/5 false‐negative biopsies, GCNIS was found on histological revision using immunohistochemistry and 2/5 biopsies were inadequate because of too small size. The estimated cumulative incidence rate of second tumour after 20 years of follow‐up was 0.95% (95% CI 0.10%–1.8%) compared with 2.9% (95% CI 1.3%–4.4%) among the non‐biopsied TGCT patients (P = 0.012). The estimates should be viewed with caution due to the small number of patients with metachronous TGCT. Conclusions: Optimized diagnostic procedures improved the detection rate of GCNIS in patients with TGCT and minimized their risk of developing metachronous bilateral cancer. Urologists should be aware of the importance of careful tissue excision (to avoid mechanical compression) and the need of adequate biopsy size. Performing contralateral biopsies is beneficial for patients' care and should be offered as a part of their management. [ABSTRACT FROM AUTHOR]

Objective: To investigate differences in bacterial distribution and resistance patterns of relevant pathogens in skin and tissue infections among migrants compared to nonmigrants. Methods: The population is based on a cohort of migrants who obtained residence as refugees or family‐reunited migrants in Denmark between January 1993 and December 2015. The cohort was linked to positive swabs and tissue cultures collected from hospitals and general practitioners between the years 2000 and 2016 at the Department of Microbiology, University Hospital Hvidovre, Denmark. We calculated odds ratios for pathogen distribution and resistance patterns using logistic regression by comparing migrants with nonmigrants. Results: In total, 43,770 pathogens from 37,276 individuals were included, with Staphylococcus aureus being the most common bacterium. Migrants had higher odds of infections with Enterobacterales than nonmigrants (OR 1.42, 95% CI: 1.23–1.63) and lower odds of beta‐haemolytic Streptococci (OR 0.79, 95% CI: 0.73–0.86). Family‐reunited migrants and refugees had higher odds of methicillin‐resistant S. aureus (MRSA) than nonmigrants (OR 5.01, 95% CI: 3.73–6.73 and OR 3.66, 95% CI: 2.61–5.13). This was more pronounced in female migrants. The odds of ciprofloxacin‐resistant Enterobacterales were higher in both family‐reunited migrants and refugees than in nonmigrants (OR 2.21, 95% CI: 1.34–3.64 and OR 2.17, 95% CI: 1.34–3.52). Conclusions: The prevalence of MRSA and ciprofloxacin‐resistant Enterobacterales was higher among family‐reunited migrants and refugees than in nonmigrants. Our findings suggest an increased awareness for AMR in migrants. [ABSTRACT FROM AUTHOR]

Background: Quarterly intramuscular injections with long‐acting testosterone undecanoate (TU) provide stable serum testosterone concentrations over time and are therefore preferred by many testosterone‐deficient patients. However, the use of long‐acting TU in elderly patients is limited due to lack of safety and feasibility studies. Objective: To investigate long‐acting TU pharmacokinetics and assess differences in treatment regimens and risk of adverse outcomes in younger versus elderly testosterone‐deficient patients. Materials and methods: Single‐center longitudinal observational study. Patients who initiated long‐acting TU treatment between 2005 and 2010 were included. Elderly patients were born before 1956 and younger patients between 1965 and 1985. TU dose was adjusted yearly through shortening or prolongation of time between injections. Treatment targets were as follows: (1) free testosterone between 0 and −1 SD from the age‐adjusted mean, (2) no symptoms of testosterone deficiency, and (3) hematocrit within the normal range. Results: The study population consisted of 63 elderly and 63 younger patients. Median follow‐up time during testosterone replacement was 12.1 years. Increasing intervals between TU injections were performed 44% more often in the elderly compared to younger patients and time between TU injections were prolonged 4% more in the elderly patients. The hematocrit, as well as the hematocrit for a given serum testosterone (hematocrit: testosterone ratio), increased with treatment time but did not differ between age groups. During follow‐up, 40% of patients—both elderly and younger—experienced polycythemia. Risk of polycythemia did not differ with age. Discussion and conclusion: An increased number of adjustments of TU dose are necessary in elderly patients in order to reach treatment targets. TU treatment in elderly testosterone‐deficient patients is not associated with an increased risk of polycythemia compared to younger patients if age‐adjusted treatment targets are reached. [ABSTRACT FROM AUTHOR]

Background: Spermatogenesis depends on stimulation by follicle‐stimulating hormone (FSH) which binds to FSH receptors (FSHR) on testicular Sertoli cells. Three FSH‐related single‐nucleotide polymorphisms (SNPs), FSHB ‐211G>T (rs10835638), FSHR ‐29G>A (rs1394205) and FSHR 2039A>G (rs6166) affect FSH action, and have been suggested to affect testicular function, but the evidence is uncertain. Objective: To describe the associations between the three SNPs and testicular function in a large and well‐characterised cohort of men from the general population. Materials and methods: A cross‐sectional study of 2020 Danish men unselected regarding testicular function. Outcome variables were semen parameters, reproductive hormones and testis size. Genotyping was done by competitive allele‐specific quantitative PCR. Differences in genotype frequencies were tested by chi‐square test and associations between genotypes and outcomes were assessed by multivariate linear regressions. Results: The SNPs affected serum FSH; carriers of the variant affecting FSH secretion (FSHB ‐211G>T) had lower FSH levels while carriers of variants affecting receptor expression (FSHR ‐29G>A) and receptor sensitivity (FSHR 2039A>G) had higher FSH levels. Carriers of FSHB ‐211G>T had lower calculated free testosterone/LH ratio. Although both FSHB ‐211G>T and FSHR 2039A>G were associated with smaller testis size, no clear association was detected in relation to any semen parameters, except a lower total number of morphologically normal spermatozoa in the heterozygous carriers of the FSHB ‐211G>T Discussion and Conclusion: The studied polymorphisms have only minor modulating influence on testis size and function in healthy men. We detected subtle effects of the three SNPs on FSH levels, but also effects of FSHB ‐211G>T on calculated free testosterone/LH ratio, compatible with altered Leydig cell function. Thus, the role of these FSH‐related polymorphisms is complex and modest in men with normal testicular function, but the possible importance of FSH polymorphisms in men with impaired testicular function should be evaluated in future studies in more detail. [ABSTRACT FROM AUTHOR]

We present a model-based approach to the analysis of agreement between different raters in a situation where all raters have supplied ordinal ratings of the same cases in a sample. It is assumed that no "gold standard" is available. The model is an ordinal regression model with random effects-a so-called rating scale model. The model includes case-specific parameters that allow each case his or hers own level (disease severity). It also allows raters to have different propensities to score a given set of individuals more or less positively-the rater level. Based on the model, we suggest quantifying the rater variation using the median odds ratio. This allows expressing the variation on the same scale as the observed ordinal data. An important example that will serve to motivate and illustrate the proposed model is the study of breast cancer diagnosis based on screening mammograms. The purpose of the assessment is to detect early breast cancer in order to obtain improved cancer survival. In the study, mammograms from 148 women were evaluated by 110 expert radiologists. The experts were asked to rate each mammogram on a 5-point scale ranging from "normal" to "probably malignant." [ABSTRACT FROM AUTHOR]

This paper describes a new approach to the estimation in a logistic regression model with two crossed random effects where special interest is in estimating the variance of one of the effects while not making distributional assumptions about the other effect. A composite likelihood is studied. For each term in the composite likelihood, a conditional likelihood is used that eliminates the influence of the random effects, which results in a composite conditional likelihood consisting of only one-dimensional integrals that may be solved numerically. Good properties of the resulting estimator are described in a small simulation study. [ABSTRACT FROM AUTHOR]

Objective To evaluate revised criteria for polycystic ovarian morphology ( PCOM) in the diagnosis of polycystic ovary syndrome ( PCOS) in anovulatory infertility. Design Prospective cohort study. Patients WHO Group II anovulatory infertile women ( n = 75). Measurements Clinical, sonographic and endocrine parameters, including anti- Müllerian hormone ( AMH). Results The Rotterdam criteria for PCOM (antral follicle count ( AFC) ≥12 and/or ovarian volume >10 ml) were fulfilled in 93% of the women. The PCOM prevalence was 68% when increasing the threshold to AFC >20 and 76% according to an AMH-based threshold of >35 pmol/l. The most recently proposed AFC ≥ 25 threshold reduced the PCOM prevalence to 52% ( n = 39), leaving 48% ( n = 36) without features of PCOM. Comparing the 36 women with non- PCOM with the 39 women in the PCOM group according to AFC ≥ 25, 22% vs 59% ( P = 0·001) had serum LH >10 IU/l, 11% vs 41% ( P = 0·003) had an LH/ FSH ratio >2 and 19% vs 41% ( P = 0·04) had hirsutism and/or elevated total testosterone, free testosterone, and/or androstenedione. The non- PCOM group included significantly more women with secondary infertility. The median AMH in the non- PCOM group was 47 pmol/l, which was twofold lower than in the PCOM group but above the upper limit of normo-ovulatory women. Conclusions According to a revised threshold of 25 follicles, almost half the anovulatory infertile women do not have PCOM. The characteristics of these women may be compatible with hypothalamic anovulation, but according to AMH levels, the ovaries remain multifollicular. Perspectives A better distinction between hypothalamic amenorrhoea and PCOS could improve treatment strategies for anovulatory infertility. [ABSTRACT FROM AUTHOR]

Aim To construct new Danish growth charts for 0- to 20-year-olds and to compare them with Danish references from 1982 and with World Health Organization ( WHO) standards for children aged 0-5 years from 2006, by applying similar inclusion and exclusion criteria. Methods Anthropometric data from three contemporary Danish population-based studies were combined. References for height were based on healthy Caucasian children born at term. A total of 12 671 height measurements (8055 in boys and 4616 in girls) were included. Reference charts were developed using the generalised additive models for location, scale and shape. Results From prepubertal ages, a secular increase in height was observed for both genders. The differences were most pronounced in puberty, and final heights were increased by 1.4 cm in boys and 2.9 cm in girls compared to 1982 references. In boys, but not girls an upward shift in body mass index ( BMI) above median levels was found. Reference curves for height were superimposable with standard curves based on the selective WHO criteria. Danish children were longer/taller and heavier and they had larger head circumferences than those reported in the recent multiethnic WHO standards. Conclusion We recommend national implementation of these contemporary 2014 Danish references for anthropometric measurements. [ABSTRACT FROM AUTHOR]

Background The diagnosis of androgen deficiency is based on clinical features and confirmatory low serum testosterone levels. In early primary testicular failure, a rise in serum LH levels suggests inadequate androgen action for the individual's physiological requirements despite a serum testosterone level within the normal range. The combined evaluation of serum LH and testosterone levels in the evaluation of testicular failure has not been widely advocated. Patients Seven hundred and six healthy males and 39 patients with known primary hypogonadism due to Klinefelter's syndrome and SRY-positive 46,XX karyotypes were included in the study. Design Testosterone, oestradiol and LH serum concentrations were measured in all individuals. Based on the 706 healthy males two-dimensional bivariate LH-testosterone reference charts were constructed. Results Despite a median serum total and free testosterone and oestradiol levels being reduced ( P < 0·001) and LH levels elevated ( P < 0·001) in Klinefelter's syndrome and 46,XX-males, many subjects (69%) had total testosterone within the reference range. However, using the bivariate charts all subjects lay outside the 97·5 percentile. Conclusion Bivariate LH and testosterone charts are useful in the evaluation of men with known primary testicular failure due to sex chromosomal aneuploidy in whom evaluation based on testosterone measurement in isolation underestimates the prevalence of hypogonadism. It is, however, important to emphasize that isolated use of the bivariate evaluation should not form the basis for androgen substitution therapy. Further studies are needed in order to evaluate the use of bivariate LH and testosterone charts in the assessment of any younger man with possible primary testicular failure. [ABSTRACT FROM AUTHOR]

Objectives: Chronic lymphocytic leukemia (CLL) is an incurable disease with a highly variable clinical course. IgVH mutational status, chromosomal aberrations, CD38 expression and ZAP-70 expression are prognostic markers in CLL, however, they are not exclusively confined to this disease. We recently identified a novel CLL-specific gene (CLL upregulated gene1, CLLU1) that is exclusively upregulated in CLL cells. Here we describe our evaluation of the prognostic significance of CLLU1 in CLL. Methods: A cohort of 59 previously untreated CLL patients was studied. We determined the expression levels of two CLLU1 transcripts, cDNA1 and CDS, by quantitative RT-PCR. The relation between CLLU1 expression and time to therapy, overall survival and presence or absence of ZAP-70, CD38, chromosomal aberrations or IgVH mutations in the 59 patients was analyzed. Results: Analyzed as a continuous, quantitative parameter CLLU1 levels significantly predicted time from diagnosis to initiation of therapy ( P ≤ 0.0003) Analyzed as a categorical parameter, by segregation of the patients into groups with cDNA1 or CDS expression above or below the median, the CLLU1 levels significantly predicted time from diagnosis to initiation of therapy ( P = 0.001) and predicted overall survival with borderline significance ( P ≤ 0.05). Patient stratification according to clinical stage, cytogenetics, IgVH mutational status, ZAP-70 and CD38, demonstrated significantly increased CLLU1 expression in all investigated CLL poor risk groups. CLLU1 expression levels contributed additional prognostic information to ZAP-70-positive patients. Conclusions: CLLU1 is the first identified CLL specific gene. The CLLU1 mRNA expression level can predict time to initiation of treatment and survival in CLL patients. [ABSTRACT FROM AUTHOR]

OBJECTIVE Focus on long-term side-effects after cancer therapy in childhood has become of the utmost importance. The hypothalamic-pituitary thyroid (HPT) axis is exposed to irradiation when some children are treated for acute lymphoblastic leukaemia (ALL) with prophylactic cranial irradiation (CIR). Whether this treatment causes hypofunction of the HPT axis remains controversal. DESIGN We measured plasma levels of total T3 (T3), total T4 (T4) and TSH before stimulation with TRH and plasma levels of TSH, 30 and 150 minutes after stimulation with TRH in 95 patients in first continuous remission of childhood ALL. PATIENTS Patients diagnosed with ALL before the age of 15 years between 1970 and 1991 and who were in first continuous remission and off treatment for at least one year were studied. The children were aged between 0·5 and 14·8 years (median: 3·9) at diagnosis of ALL. Thyroid function was assessed between 1·2 and 18·3 years (median: 7·6) after completion of therapy. MEASUREMENTS We measured T4 levels before, and compared TSH levels before and after, stimulation with TRH in patients who were treated with prophylactic CIR (15–24 Gy) (n = 38) (CIR group) with patients who were treated with chemotherapy only (n = 57) (non-CIR group). RESULTS We found that T3 and T4 levels were normal in all individuals (excluding the women who were on oral contraceptives). The median time from end of treatment to time at follow-up was 9·1 years in the non-CIR group vs. 4·2 years in the CIR group (P < 0·001), and the effect on follow-up time was significant (P = 0·04). It was estimated that just after irradiation, the TSH levels before and 30 and 150 minutes after TRH stimulation was 49% lower in the CIR group; however, after 4·0 years, TSH levels were not significantly different between the two groups. Although within normal limits, the T4 levels were significantly higher in the CIR group compared to the non-CIR group (P = 0·003). It was estimated that, just after the end of treatment, T4 was 19·9% higher in the CIR group. However, in the CIR group, the T4 level decreased significantly over time with -1·5% per year (P = 0·025), while the difference in the non-CIR group was not significant. There was no correlation between T4 and TSH levels and sex, age at diagnosis, age at the end of treatment or age at follow-up. CONCLUSIONS We conclude that, in our cohort of survivors of childhood ALL, prophylactic cranial irradiation of the central nervous system did not have an adverse effect on hypothalamo-pituitary-thyroid function within a median follow-up time of 8 years. [ABSTRACT FROM AUTHOR]

Aims: The aim of this retrospective study was to assess whether and how the age of the woman affects the quality and developmental potential of the oocytes and embryos in an ART program.Method and Material: A total of 878 IVF cycles was included as a consecutive series of single transfers (n=292), dual transfers (n=366) and triple transfers (n=220), where all the transferred embryos in each cycle were of identical quality score and identical cleavage stage.Results: We found a highly significant decrease in oocyte recovery with increasing age with about one oocyte per 2.3 years (95% CI 1.8 years to 3.1 years, p<0.0001). Further, we found that the number of oocytes that cleaved declined significantly with increasing age with one per 3.7 years (95% CI 2.7 years to 5.5 years, p<0.0001). This decline was mainly due to the decline in number of oocytes retrieved as the ratio of aspirated oocytes that cleaved with increasing age (approx. -0.04/10 year 95% CI: -0.10; +0.009) was not significantly different (p=0.10). The percentage of transfers using fragmented embryos did not increase significantly with increasing age (p=0.08). The odds of fragmentation increased by 3% per year. The average number of embryos transferred decreased significantly (p=0.03) with age from approximately 2.1 at the age of 25 to approximately 1.8 at the age of 40. In a selected subgroup of embryos all consisting of good quality embryos, a significant decrease was found in implantation rate with increasing age (approx. -0.08/10 years, 95% CI: -1.6; +0.00, p=0.05). Of the 357 pregnancies achieved in this study we found a significantly decreased ongoing pregnancy rate and a significantly increased abortion rate with increasing age (p=0.03). The decrease in the rate of ongoing pregnancies was almost linear, decreasing by approximately 1.5% per year.Conclusions: We conclude that age has an impact throughout a woman's reproductive life and that it is important to realize that the age-related decline in fertility may start already in the late twenties and not in the mid-thirties as is generally assumed. [ABSTRACT FROM AUTHOR]

Inter-observer variation in andrological examination by 10 clinical investigators from five Nordic and Baltic countries was investigated. In addition, information on intra-observer variation was obtained for six of the 10 investigators. Testicular size was measured using Prader’s orchidometer and one of the investigators also performed an ultrasound estimate of testicular size. A highly significant difference (p < 0.001) between observers was found with an inter-observer error of 16% in estimating testicular size in 23 young men. The difference in the estimate tended to increase with increasing testicular size. There was no significant intra-observer difference in two measurements performed on consecutive days. Only differences in median testis size, which were greater than 31% between measurements by two investigators, were found to be significant at the 5% level. The ultrasound estimate of testicular size was significantly lower than the orchidometer estimate, with a mean difference of 3.6 mL for the left testis and 4.3 mL for the right testis. Tanner staging of genitalia and diagnosis of a varicocele was subject to great inter-observer variation, and for the diagnosis of varicocele only one-third of the investigators was able to reproduce their results on a second examination. In conclusion, it was found that the clinical andrological examination of young men is subject to great inter-observer variation. This should be kept in mind when results from different studies are compared as well as in daily clinical practice. [ABSTRACT FROM AUTHOR]