Prevalence and 1-year incidence of HIV-associated neurocognitive disorder (HAND) in adults aged ≥50 years attending standard HIV clinical care in Kilimanjaro, Tanzania.

OBJECTIVES: HIV-associated neurocognitive disorders (HANDs) are prevalent in older people living with HIV (PLWH) worldwide. HAND prevalence and incidence studies of the newly emergent population of combination antiretroviral therapy (cART)-treated older PLWH in sub-Saharan Africa are currently lacking. We aimed to estimate HAND prevalence and incidence using robust measures in stable, cART-treated older adults under long-term follow-up in Tanzania and report cognitive comorbidities. DESIGN: Longitudinal study. PARTICIPANTS: A systematic sample of consenting HIV-positive adults aged ≥50 years attending routine clinical care at an HIV Care and Treatment Centre during March-May 2016 and followed up March-May 2017. MEASUREMENTS: HAND by consensus panel Frascati criteria based on detailed locally normed low-literacy neuropsychological battery, structured neuropsychiatric clinical assessment, and collateral history. Demographic and etiological factors by self-report and clinical records. RESULTS: In this cohort (n = 253, 72.3% female, median age 57), HAND prevalence was 47.0% (95% CI 40.9-53.2, n = 119) despite well-managed HIV disease (Mn CD4 516 (98-1719), 95.5% on cART). Of these, 64 (25.3%) were asymptomatic neurocognitive impairment, 46 (18.2%) mild neurocognitive disorder, and 9 (3.6%) HIV-associated dementia. One-year incidence was high (37.2%, 95% CI 25.9 to 51.8), but some reversibility (17.6%, 95% CI 10.0-28.6 n = 16) was observed. CONCLUSIONS: HAND appear highly prevalent in older PLWH in this setting, where demographic profile differs markedly to high-income cohorts, and comorbidities are frequent. Incidence and reversibility also appear high. Future studies should focus on etiologies and potentially reversible factors in this setting.

Low-dose radiotherapy to the lungs using an interventional radiology C-arm fluoroscope: Monte Carlo treatment planning and dose measurements in a postmortem subject.

Objective.The goal of this study was to use Monte Carlo (MC) simulations and measurements to investigate the dosimetric suitability of an interventional radiology (IR) c-arm fluoroscope to deliver low-dose radiotherapy to the lungs.Approach.A previously-validated MC model of an IR fluoroscope was used to calculate the dose distributions in a COVID-19-infected patient, 20 non-infected patients of varying sizes, and a postmortem subject. Dose distributions for PA, AP/PA, 3-field and 4-field treatments irradiating 95% of the lungs to a 0.5 Gy dose were calculated. An algorithm was created to calculate skin entrance dose as a function of patient thickness for treatment planning purposes. Treatments were experimentally validated in a postmortem subject by using implanted dosimeters to capture organ doses.Main results.Mean doses to the left/right lungs for the COVID-19 CT data were 1.2/1.3 Gy, 0.8/0.9 Gy, 0.8/0.8 Gy and 0.6/0.6 Gy for the PA, AP/PA, 3-field, and 4-field configurations, respectively. Skin dose toxicity was the highest probability for the PA and lowest for the 4-field configuration. Dose to the heart slightly exceeded the ICRP tolerance; all other organ doses were below published tolerances. The AP/PA configuration provided the best fit for entrance skin dose as a function of patient thickness (R2 = 0.8). The average dose difference between simulation and measurement in the postmortem subject was 5%.Significance.An IR fluoroscope should be capable of delivering low-dose radiotherapy to the lungs with tolerable collateral dose to nearby organs.

Monte Carlo simulations and phantom validation of low-dose radiotherapy to the lungs using an interventional radiology C-arm fluoroscope.

PURPOSE: To use MC simulations and phantom measurements to investigate the dosimetry of a kilovoltage x-ray beam from an IR fluoroscope to deliver low-dose (0.3-1.0 Gy) radiotherapy to the lungs. MATERIALS AND METHODS: PENELOPE was used to model a 125 kV, 5.94 mm Al HVL x-ray beam produced by a fluoroscope. The model was validated through depth-dose, in-plane/cross-plane profiles and absorbed dose at 2.5-, 5.1-, 10.2- and 15.2-cm depths against the measured beam in an acrylic phantom. CT images of an anthropomorphic phantom thorax/lungs were used to simulate 0.5 Gy dose distributions for PA, AP/PA, 3-field and 4-field treatments. DVHs were generated to assess the dose to the lungs and nearby organs. Gafchromic film was used to measure doses in the phantom exposed to PA and 4-field treatments, and compared to the MC simulations. RESULTS: Depth-dose and profile results were within 3.2% and 7.8% of the MC data uncertainty, respectively, while dose gamma analysis ranged from 0.7 to 1.0. Mean dose to the lungs were 1.1-, 0.8-, 0.9-, and 0.8- Gy for the PA, AP/PA, 3-field, and 4-field after isodose normalization to cover âˆ¼ 95% of each lung volume. Skin dose toxicity was highest for the PA and lowest for the 4-field, and both arrangements successfully delivered the treatment on the phantom. However, the dose distribution for the PA was highly non-uniform and produced skin doses up to 4 Gy. The dose distribution for the 4-field produced a uniform 0.6 Gy dose throughout the lungs, with a maximum dose of 0.73 Gy. The average percent difference between experimental and Monte Carlo values were -0.1% (range -3% to +4%) for the PA treatment and 0.3% (range -10.3% to +15.2%) for the 4-field treatment. CONCLUSION: A 125 kV x-ray beam from an IR fluoroscope delivered through two or more fields can deliver an effective low-dose radiotherapy treatment to the lungs. The 4-field arrangement not only provides an effective treatment, but also significant dose sparing to healthy organs, including skin, compared to the PA treatment. Use of fluoroscopy appears to be a viable alternative to megavoltage radiation therapy equipment for delivering low-dose radiotherapy to the lungs.

A higher flexibility at the SARS-CoV-2 main protease active site compared to SARS-CoV and its potentialities for new inhibitor virtual screening targeting multi-conformers.

The main-protease (Mpro) catalyzes a crucial step for the SARS-CoV-2 life cycle. The recent SARS-CoV-2 presents the main protease (MCoV2pro) with 12 mutations compared to SARS-CoV (MCoV1pro). Recent studies point out that these subtle differences lead to mobility variances at the active site loops with functional implications. We use metadynamics simulations and a sort of computational analysis to probe the dynamic, pharmacophoric and catalytic environment differences between the monomers of both enzymes. So, we verify how much intrinsic distinctions are preserved in the functional dimer of MCoV2pro, as well as its implications for ligand accessibility and optimized drug screening. We find a significantly higher accessibility to open binding conformers in the MCoV2pro monomer compared to MCoV1pro. A higher hydration propensity for the MCoV2pro S2 loop with the A46S substitution seems to exercise a key role. Quantum calculations suggest that the wider conformations for MCoV2pro are less catalytically active in the monomer. However, the statistics for contacts involving the N-finger suggest higher maintenance of this activity at the dimer. Docking analyses suggest that the ability to vary the active site width can be important to improve the access of the ligand to the active site in different ways. So, we carry out a multiconformational virtual screening with different ligand bases. The results point to the importance of taking into account the protein conformational multiplicity for new promissors anti MCoV2pro ligands. We hope these results will be useful in prospecting, repurposing and/or designing new anti SARS-CoV-2 drugs.Communicated by Ramaswamy H. Sarma.

Hepatocellular carcinoma biomarkers, an imminent need.

Hepatocellular carcinoma (HCC) is the most common malignant neoplasm of the liver and one of the deadliest cancers worldwide. The identification of novel, highly specific and more sensitive biomarkers for HCC is crucial because existing ones are deficient and non-confirmatory without histological biopsy or imaging techniques.

Role of ventilatory control instability in children with sleep-disordered breathing.

BACKGROUND AND OBJECTIVE: The contribution of non-anatomical factors, such as ventilatory control instability (i.e. LG), to the pathogenesis of obstructive SDB in children is unclear. Therefore, we aimed to identify the relationship between LG and severity of SDB, demographic, anthropometric and anatomical characteristics in a clinically representative cohort of children. METHODS: Children (aged 3-18 years) with various severities of SDB (n = 110) and non-snoring controls (n = 36) were studied. Children were grouped according to their OAHI. Anthropometric and upper airway anatomical characteristics were measured. Spontaneous sighs were identified on polysomnography and LG, a measure of the sensitivity of the negative feedback loop that controls ventilation, was estimated by fitting a mathematical model of ventilatory control to the post-sigh ventilatory pattern. RESULTS: There was no difference in LG between controls and any of the SDB severity groups. However, LG was significantly lower in children with larger tonsils (tonsil grade 4) compared with children with smaller tonsils (tonsil grade 1) (median LG (range): 0.25 (0.20-0.42) vs 0.32 (0.25-0.44); P = 0.009) and in children with a modified Mallampati score of class III/IV compared with class I (0.28 (0.24-0.33) vs 0.37 (0.27-0.44); P = 0.009). CONCLUSION: A direct relationship was not found between the severity of paediatric SDB and LG. However, an altered ventilatory control sensitivity may contribute to SDB in a subgroup of children depending on their degree of anatomical compromise of the airway.

Journey towards a personalised medicine approach for OSA: Can a similar approach to adult OSA be applied to paediatric OSA?

The concept of personalised medicine is likely to revolutionise the treatment of adult obstructive sleep apnoea as a result of recent advances in the understanding of disease heterogeneity by identifying clinical phenotypes, pathophysiological endotypes, biomarkers and treatable traits. Children with the condition show a similar level of heterogeneity and paediatric obstructive sleep apnoea would also benefit from a more targeted approach to diagnosis and management. This review aims to summarise the adult literature on the phenotypes and endotypes of obstructive sleep apnoea and assess whether a similar approach may also be suitable to guide the development of new diagnostic and management approaches for paediatric obstructive sleep apnoea.

Kisspeptin treatment induces gonadotropic responses and rescues ovulation in a subset of preclinical models and women with polycystic ovary syndrome.

STUDY QUESTION: Can kisspeptin treatment induce gonadotrophin responses and ovulation in preclinical models and anovulatory women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Kisspeptin administration in some anovulatory preclinical models and women with PCOS can stimulate reproductive hormone secretion and ovulation, albeit with incomplete efficacy. WHAT IS KNOWN ALREADY: PCOS is a prevalent, heterogeneous endocrine disorder, characterized by ovulatory dysfunction, hyperandrogenism and deregulated gonadotrophin secretion, in need of improved therapeutic options. Kisspeptins (encoded by Kiss1) are master regulators of the reproductive axis, acting mainly at GnRH neurons, with kisspeptins being an essential drive for gonadotrophin-driven ovarian follicular maturation and ovulation. Altered Kiss1 expression has been found in rodent models of PCOS, although the eventual pathophysiological role of kisspeptins in PCOS remains unknown. STUDY DESIGN, SIZE, DURATION: Gonadotrophin and ovarian/ovulatory responses to kisspeptin-54 (KP-54) were evaluated in three preclinical models of PCOS, generated by androgen exposures at different developmental windows, and a pilot exploratory cohort of anovulatory women with PCOS. PARTICIPANTS/MATERIALS, SETTING, METHODS: Three models of PCOS were generated by exposure of female rats to androgens at different periods of development: PNA (prenatal androgenization; N = 20), NeNA (neonatal androgenization; N = 20) and PWA (post-weaning androgenization; N = 20). At adulthood (postnatal day 100), rats were subjected to daily treatments with a bolus of KP-54 (100 µg/kg, s.c.) or vehicle for 11 days (N = 10 per model and treatment). On Days 1, 4, 7 and 11, LH and FSH responses were assessed at different time-points within 4 h after KP-54 injection, while ovarian responses, in terms of follicular maturation and ovulation, were measured at the end of the treatment. In addition, hormonal (gonadotrophin, estrogen and inhibin B) and ovulatory responses to repeated KP-54 administration, at doses of 6.4-12.8 nmol/kg, s.c. bd for 21 days, were evaluated in a pilot cohort of anovulatory women (N = 12) diagnosed with PCOS, according to the Rotterdam criteria. MAIN RESULTS AND THE ROLE OF CHANCE: Deregulated reproductive indices were detected in all PCOS models: PNA, NeNA and PWA. Yet, anovulation was observed only in NeNA and PWA rats. However, while anovulatory NeNA rats displayed significant LH and FSH responses to KP-54 (P < 0.05), which rescued ovulation, PWA rats showed blunted LH secretion after repeated KP-54 injection and failed to ovulate. In women with PCOS, KP-54 resulted in a small rise in LH (P < 0.05), with an equivalent elevation in serum estradiol levels (P < 0.05). Two women showed growth of a dominant follicle with subsequent ovulation, one woman displayed follicle growth but not ovulation and desensitization was observed in another patient. No follicular response was detected in the other women. LIMITATIONS, REASONS FOR CAUTION: While three different preclinical PCOS models were used in order to capture the heterogeneity of clinical presentations of the syndrome, it must be noted that rat models recapitulate many but not all the features of this condition. Additionally, our pilot study was intended as proof of principle, and the number of participants is low, but the convergent findings in preclinical and clinical studies reinforce the validity of our conclusions. WIDER IMPLICATIONS OF THE FINDINGS: Our first-in-rodent and -human studies demonstrate that KP-54 administration in anovulatory preclinical models and women with PCOS can stimulate reproductive hormone secretion and ovulation, albeit with incomplete efficacy. As our rat models likely reflect the diversity of PCOS phenotypes, our results argue for the need of personalized management of anovulatory dysfunction in women with PCOS, some of whom may benefit from kisspeptin-based treatments. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by research agreements between Ferring Research Institute and the Universities of Cordoba and Edinburgh. K.S. was supported by the Wellcome Trust Scottish Translational Medicine and Therapeutics Initiative (STMTI). Some of this work was undertaken in the MRC Centre for Reproductive Health which is funded by the MRC Centre grant MR/N022556/1. M.T.-S. is a member of CIBER Fisiopatología de la Obesidad y Nutrición, which is an initiative of Instituto de Salud Carlos III. Dr Mannaerts is an employee of Ferring International PharmaScience Center (Copenhagen, Denmark), and Drs Qi, van Duin and Kohout are employees of the Ferring Research Institute (San Diego, USA). Dr Anderson and Dr Tena-Sempere were recipients of a grant support from the Ferring Research Institute, and Dr Anderson has undertaken consultancy work and received speaker fees outside this study from Merck, IBSA, Roche Diagnostics, NeRRe Therapeutics and Sojournix Inc. Dr Skorupskaite was supported by the Wellcome Trust through the Scottish Translational Medicine and Therapeutics Initiative 102419/Z/13/A. The other authors have no competing interest.

Extracellular NK histones promote immune cell anti-tumor activity by inducing cell clusters through binding to CD138 receptor.

BACKGROUND: Natural killer (NK) cells are important anti-tumor cells of our innate immune system. Their anti-cancer activity is mediated through interaction of a wide array of activating and inhibitory receptors with their ligands on tumor cells. After activation, NK cells also secrete a variety of pro-inflammatory molecules that contribute to the final immune response by modulating other innate and adaptive immune cells. In this regard, external proteins from NK cell secretome and the mechanisms by which they mediate these responses are poorly defined. METHODS: TRANS-stable-isotope labeling of amino acids in cell culture (TRANS-SILAC) combined with proteomic was undertaken to identify early materials transferred between cord blood-derived NK cells (CB-NK) and multiple myeloma (MM) cells. Further in vitro and in vivo studies with knock-down of histones and CD138, overexpression of histones and addition of exogenous histones were undertaken to confirm TRANS-SILAC results and to determine functional roles of this material transferred. RESULTS: We describe a novel mechanism by which histones are actively released by NK cells early after contact with MM cells. We show that extracellular histones bind to the heparan sulfate proteoglycan CD138 on the surface of MM cells to promote the creation of immune-tumor cell clusters bringing immune and MM cells into close proximity, and thus facilitating not only NK but also T lymphocyte anti-MM activity. CONCLUSION: This study demonstrates a novel immunoregulatory role of NK cells against MM cells mediated by histones, and an additional role of NK cells modulating T lymphocytes activity that will open up new avenues to design future immunotherapy clinical strategies.

Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials.

BACKGROUND: Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) generally have a high symptom burden and poor health-related quality of life, often requiring recurring systemic corticosteroid use and repeated sinus surgery. Dupilumab is a fully human monoclonal antibody that inhibits signalling of interleukin (IL)-4 and IL-13, key drivers of type 2 inflammation, and has been approved for use in atopic dermatitis and asthma. In these two studies, we aimed to assess efficacy and safety of dupilumab in patients with CRSwNP despite previous treatment with systemic corticosteroids, surgery, or both. METHODS: LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52 were two multinational, multicentre, randomised, double-blind, placebo-controlled, parallel-group studies assessing dupilumab added to standard of care in adults with severe CRSwNP. SINUS-24 was done in 67 centres in 13 countries, and SINUS-52 was done in 117 centres in 14 countries. Eligible patients were 18 years or older with bilateral CRSwNP and symptoms despite intranasal corticosteroid use, receiving systemic corticosteroids in the preceding 2 years, or having had sinonasal surgery. Patients in SINUS-24 were randomly assigned (1:1) to subcutaneous dupilumab 300 mg or placebo every 2 weeks for 24 weeks. Patients in SINUS-52 were randomly assigned (1:1:1) to dupilumab 300 mg every 2 weeks for 52 weeks, dupilumab every 2 weeks for 24 weeks and then every 4 weeks for the remaining 28 weeks, or placebo every 2 weeks for 52 weeks. All patients were randomly assigned centrally with a permuted block randomisation schedule. Randomisation was stratified by asthma or non-steroidal anti-inflammatory drug-exacerbated respiratory disease status at screening, previous surgery at screening, and country. Patients with or without comorbid asthma were included. Coprimary endpoints were changes from baseline to week 24 in nasal polyp score (NPS), nasal congestion or obstruction, and sinus Lund-Mackay CT scores (a coprimary endpoint in Japan), done in an intention-to-treat population. Safety was assessed in a pooled population of both dupilumab groups in SINUS-52 up to week 24 and the dupilumab group in SINUS-24 and the placebo groups in both studies until week 24. The trials are complete and registered at ClinicalTrials.gov, NCT02912468 and NCT02898454. FINDINGS: Between Dec 5, 2016, and Aug 3, 2017, 276 patients were enrolled in SINUS-24, with 143 in the dupilumab group and 133 in the placebo group receiving at least one study drug dose. Between Nov 28, 2016, and Aug 28, 2017, 448 patients were enrolled in SINUS-52, with 150 receiving at least one dose of dupilumab every 2 weeks, 145 receiving at least one dose of dupilumab every 2 weeks for 24 weeks and every 4 weeks until week 52, and 153 receiving at least one dose of placebo. Dupilumab significantly improved the coprimary endpoints in both studies. At 24 weeks, least squares mean difference in NPS of dupilumab treatment versus placebo was -2·06 (95% CI -2·43 to -1·69; p<0·0001) in SINUS-24 and -1·80 (-2·10 to -1·51; p<0·0001) in SINUS-52; difference in nasal congestion or obstruction score was -0·89 (-1·07 to -0·71; p<0·0001) in SINUS-24 and -0·87 (-1·03 to -0·71; p<0·0001) in SINUS-52; and difference in Lund-Mackay CT scores was -7·44 (-8·35 to -6·53; p<0·0001) in SINUS-24 and -5·13 (-5·80 to -4·46; p<0·0001) in SINUS-52. The most common adverse events (nasopharyngitis, worsening of nasal polyps and asthma, headache, epistaxis, and injection-site erythema) were more frequent with placebo. INTERPRETATION: In adult patients with severe CRSwNP, dupilumab reduced polyp size, sinus opacification, and severity of symptoms and was well tolerated. These results support the benefits of adding dupilumab to daily standard of care for patients with severe CRSwNP who otherwise have few therapeutic options. FUNDING: Sanofi and Regeneron Pharmaceuticals.

De novo loss-of-function KCNMA1 variants are associated with a new multiple malformation syndrome and a broad spectrum of developmental and neurological phenotypes.

KCNMA1 encodes the large-conductance Ca2+- and voltage-activated K+ (BK) potassium channel α-subunit, and pathogenic gain-of-function variants in this gene have been associated with a dominant form of generalized epilepsy and paroxysmal dyskinesia. Here, we genetically and functionally characterize eight novel loss-of-function (LoF) variants of KCNMA1. Genome or exome sequencing and the participation in the international Matchmaker Exchange effort allowed for the identification of novel KCNMA1 variants. Patch clamping was used to assess functionality of mutant BK channels. The KCNMA1 variants p.(Ser351Tyr), p.(Gly356Arg), p.(Gly375Arg), p.(Asn449fs) and p.(Ile663Val) abolished the BK current, whereas p.(Cys413Tyr) and p.(Pro805Leu) reduced the BK current amplitude and shifted the activation curves toward positive potentials. The p.(Asp984Asn) variant reduced the current amplitude without affecting kinetics. A phenotypic analysis of the patients carrying the recurrent p.(Gly375Arg) de novo missense LoF variant revealed a novel syndromic neurodevelopmental disorder associated with severe developmental delay, visceral and cardiac malformations, connective tissue presentations with arterial involvement, bone dysplasia and characteristic dysmorphic features. Patients with other LoF variants presented with neurological and developmental symptoms including developmental delay, intellectual disability, ataxia, axial hypotonia, cerebral atrophy and speech delay/apraxia/dysarthria. Therefore, LoF KCNMA1 variants are associated with a new syndrome characterized by a broad spectrum of neurological phenotypes and developmental disorders. LoF variants of KCNMA1 cause a new syndrome distinctly different from gain-of-function variants in the same gene.

Spinal Cord Diffuse Midline Glioma in a 4-Year-Old Boy.

OBJECTIVE: We report a child presenting with spinal myelopathy secondary to H3K27M mutant diffuse midline glioma. CASE REPORT: A 4-year-old boy presented with a 3-week history of progressive gait difficulty. Examination revealed bilateral hand and lower extremity weakness, left leg hypertonia with ankle clonus, and a right hemisensory deficit. Magnetic resonance imaging of neuroaxis showed cervical and thoracic spinal cord with expansion and irregular areas of enhancement. Serum and cerebrospinal fluid studies were unremarkable for infectious, autoimmune, inflammatory, and neoplastic causes but showed mild cerebrospinal fluid pleocytosis, hypoglycorrhachia, and high protein level. A thoracic cord biopsy revealed a diffuse midline glioma (World Health Organization grade IV). Consequently, the tumor involved intracranial structures and patient died within 4 months after diagnosis. CONCLUSION: High-grade spinal cord gliomas are very rare but should be considered in the differential diagnosis of pediatric myelopathy. Tissue biopsy is recommended in indeterminate cases to facilitate diagnosis and to guide management.

Does the dose of iodine-131 influence the incidence of Graves' ophthalmopathy?

BACKGROUND: Radioactive iodine-131 (RAI) is an established treatment for patients with Graves' hyperthyroidism. RAI is reported to be associated with a 20-30% incidence of development or exacerbation of Graves' ophthalmopathy (GO). This study compares the progression of GO in patients who had evidence or no evidence of GO before RAI therapy. PATIENTS AND METHODS: Forty-eight patients were studied. One group had no evidence whereas the other group had evidence of GO before RAI treatment. All underwent RAI therapy. Group A (27 patients, 18 women, nine men, age: 19-68 with a mean of 49 years) had pre-existing exophthalmos. Group B consisted of 21 patients (13 women, eight men, age: 30-63 with a mean of 43 years) developed exophthalmos after treatment. All patients underwent RAI therapy and followed by ophthalmologists. RESULTS: The average administered dose in group A was 24.3 mCi (range: 10-36.2 mCi) compared with group B: 25.4 mCi (range: 13-35.9 mCi), P=0.60. Ten (37%) of the 27 patients in group A experienced worsening of symptoms post-treatment. There was no significant difference between the administered dose of RAI in patients with worsening symptoms, 25.1 mCi versus patients with stable symptoms, 24.5 mCi (P=0.82). However, group A developed GO symptoms earlier than group B (4.5 vs. 9.5 months), P=0.02. CONCLUSION: RAI is known to exacerbate ophthalmopathy. Our study showed it was not dose-dependent. Patients without a previous history of GO were observed to have a significantly delayed period for the development of symptoms.

Long-term results of fresh osteochondral allografts and realignment osteotomy for cartilage repair in the knee.

AIMS: The aim of this study was to report the outcome of femoral condylar fresh osteochondral allografts (FOCA) with concomitant realignment osteotomy with a focus on graft survivorship, complications, reoperation, and function. PATIENTS AND METHODS: We identified 60 patients (16 women, 44 men) who underwent unipolar femoral condylar FOCA with concomitant realignment between 1972 and 2012. The mean age of the patients was 28.9 years (10 to 62) and the mean follow-up was 11.4 years (2 to 35). Failure was defined as conversion to total knee arthroplasty, revision allograft, or graft removal. Clinical outcome was evaluated using the modified Hospital for Special Surgery (mHSS) score. RESULTS: A total of 14 grafts (23.3%) failed at a mean of 8.6 years (1.4 to 20.1). Graft survivorship was 87.3% (95% confidence interval (CI) 79.0 to 96.6), 85.0% (95% CI 75.8 to 95.3), 74.8% (95% CI 62.2 to 90.0), 65.2% (95% CI 49.9 to 85.2), and 59.8% (95% CI 43.5 to 82.1) at five, ten, 15, 20, and 25 years, respectively. A total of 23 patients (38.3%) developed complications, and 26 (43.3%) had a further operation. Persistent postoperative malalignment occurred more frequently in failed grafts (28.6% vs 4.3%; p = 0.023), and was a risk factor for graft failure (hazard ratio 6.55; 95% CI 1.61 27.71; p = 0.009). The mean mHSS score improved from 74.1 (40 to 91) preoperatively to 89.0 (66 to 100) at final follow-up (p < 0.001). CONCLUSION: Femoral condylar FOCA with concomitant realignment osteotomy provides excellent long-term graft survival and reliable functional improvement. Persistent malalignment may increase the risk for graft failure.

Prevalence of human papillomavirus types in North and Central regions of Mexico.

Human papillomavirus (HPV) is a DNA virus linked to mucosal and cutaneous carcinogenesis. More than 200 different HPV types exist. We carried out a transversal study to investigate the prevalence of HPV types in two regions of Mexico. A total of 724 genital and non-genital samples from women (F) and men (M) were studied; 241 (33%) from North-Eastern (NE) and 483 (66%) from South-Central (SC) Mexico. The overall prevalence was 87%. In genital lesions from females, the NE group showed a prevalence of HPV types 16 (37%), 6 (13%), 59 (6%), 11, 18 and 66 (5.4% each); and the SC group showed types 6 (17%), 16 (15%), 11 (14.5%), 18 (12%) and 53 (6%). In the genital lesions from males, NE group showed types 16 (38%), 6 (21%), 11 (13%) and 59 plus 31 (7.5%) and the SC group showed types 6 (25%), 11 (22%), 18 (17%) and 16 (11.5%). When the two regions were compared, a higher prevalence of low-risk HPV 6 and 11 was found in the SC region and of high-risk HPV 59, 31 and 66 (the latter can also be present in benign lesions) in the NE region. Our findings complement efforts to understand HPV demographics as a prerequisite to guide and assess the impact of preventive interventions.

Influence of Sleep Stage on LH Pulse Initiation in the Normal Late Follicular Phase and in Polycystic Ovary Syndrome.

OBJECTIVE: During the early follicular phase, sleep-related luteinizing hormone (LH) pulse initiation is positively associated with brief awakenings but negatively associated with rapid eye movement (REM) sleep. The relationship between sleep architecture and LH pulse initiation has not been assessed in other cycle stages or in women with polycystic ovary syndrome (PCOS). DESIGN AND METHODS: We performed concomitant frequent blood sampling (LH pulse analysis) and polysomnography on 8 normal women (cycle day 7-11) and 7 women with PCOS (at least cycle day 7). RESULTS: In the normal women, the 5 min preceding LH pulses contained more wake epochs and fewer REM epochs than the 5 min preceding randomly determined time points (wake: 22.3 vs. 9.1%, p = 0.0111; REM: 4.4 vs. 18.8%, p = 0.0162). However, LH pulse initiation was not related to wake or REM epochs in PCOS; instead, the 5 min preceding LH pulses contained more slow-wave sleep (SWS) than the 5 min before random time points (20.9 vs. 6.7%, p = 0.0089). Compared to the normal subjects, the women with PCOS exhibited a higher REM-associated LH pulse frequency (p = 0.0443) and a lower proportion of wake epochs 0-5 min before LH pulses (p = 0.0205). CONCLUSIONS: Sleep-related inhibition of LH pulse generation during the later follicular phase is normally weakened by brief awakenings and strengthened by REM sleep. In women with PCOS, LH pulse initiation is not appropriately discouraged by REM sleep and may be encouraged by SWS; these abnormalities may contribute to a high sleep-related LH pulse frequency in PCOS.

The Relationship Between Risk Perception and Frequency of HIV Testing Among Men Who Have Sex with Men and Transgender Women, Lima, Peru.

HIV infections in Peru are concentrated among men who have sex with men (MSM) and transgender women (TW). HIV testing rates among them remain low, delaying entrance into care. We assessed the prevalence of frequent HIV testing (at least every 6 months) and associated factors among 310 MSM and TW who attend sexual health clinics in Lima, Peru, and who reported that they were HIV seronegative or unaware of their status. Only 39% of participants tested frequently, and 22% had never tested; 29% reported that they were at low or no risk for acquiring HIV. Reporting low or no risk for acquiring HIV was associated with frequent testing (adjusted prevalence ratio [aPR] = 1.53, 95% CI 1.13-2.08); those reporting unprotected anal sex were less likely to test frequently (aPR = 0.66, 95% CI 0.50-0.87). HIV prevalence was 12% and did not vary by risk perception categories. This at-risk population tests infrequently and may not understand the risk of having unprotected sex.