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Purpose Cystic fibrosis (CF), caused by pathogenic variants in the CF transmembrane conductance regulator (CFTR), affects multiple organs including the exocrine pancreas, which is a causal contributor to cystic fibrosis–related diabetes (CFRD). Untreated CFRD causes increased CF-related mortality whereas early detection can improve outcomes. Methods Using genetic and easily accessible clinical measures available at birth, we constructed a CFRD prediction model using the Canadian CF Gene Modifier Study (CGS; n = 1,958) and validated it in the French CF Gene Modifier Study (FGMS; n = 1,003). We investigated genetic variants shown to associate with CF disease severity across multiple organs in genome-wide association studies. Results The strongest predictors included sex, CFTR severity score, and several genetic variants including one annotated to PRSS1, which encodes cationic trypsinogen. The final model defined in the CGS shows excellent agreement when validated on the FGMS, and the risk classifier shows slightly better performance at predicting CFRD risk later in life in both studies. Conclusion We demonstrated clinical utility by comparing CFRD prevalence rates between the top 10% of individuals with the highest risk and the bottom 10% with the lowest risk. A web-based application was developed to provide practitioners with patient-specific CFRD risk to guide CFRD monitoring and treatment.

Phasing of heterozygous alleles is critical for interpretation of cis-effects of disease-relevant variation. For population studies, phase is often inferred from external data but read-based phasing approaches that span long genomic distances would be more accurate because they enable both genotype and phase to be obtained from a single dataset. To demonstrate how read-based phasing can provide functional insights, we sequenced 477 individuals with Cystic Fibrosis (CF) using linked-read sequencing. We benchmark read-based phasing with different short- and long-read sequencing technologies, prioritize linked-read technology as the most informative and produce a benchmark phase call set from reference sample HG002 for the community. The 477 samples display an average phase block N50 of 4.39 Mb. We use these samples to construct a graph representation of CFTR haplotypes, which facilitates understanding of complex CF alleles. Fine-mapping and phasing of the chr7q35 trypsinogen locus associated with CF meconium ileus demonstrates a 20 kb deletion and a PRSS2 missense variant p.Thr8Ile (rs62473563) independently contribute to meconium ileus risk (p=0.0028, p=0.011, respectively) and are PRSS2 pancreas eQTLs (p=9.5e-7 and p=1.4e-4, respectively), explaining the mechanism by which these polymorphisms contribute to CF. Phase enables access to haplotypes that can be used for genome graph or reference panel construction, identification of cis-effects, and for understanding disease associated loci. The phase information from linked-reads provides a causal explanation for variation at a CF-relevant locus which also has implications for the genetic basis of non-CF pancreatitis to which this locus has been reported to contribute.

Summary Background Tezacaftor–ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8–24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor–ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor–ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation. Methods Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor–ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor–ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov ( NCT02565914 ). Findings Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor–ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor–ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor–ivacaftor-treated F/F participants versus untreated matched historical controls. Interpretation Tezacaftor–ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor–ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor–ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes. Funding Vertex Pharmaceuticals Incorporated.

Cystic fibrosis (CF), caused by pathogenic variants in the CF transmembrane conductance regulator (CFTR), affects multiple organs including the exocrine pancreas, which is a causal contributor to cystic fibrosis-related diabetes (CFRD). Untreated CFRD causes increased CF-related mortality whereas early detection can improve outcomes.Using genetic and easily accessible clinical measures available at birth, we constructed a CFRD prediction model using the Canadian CF Gene Modifier Study (CGS; n = 1,958) and validated it in the French CF Gene Modifier Study (FGMS; n = 1,003). We investigated genetic variants shown to associate with CF disease severity across multiple organs in genome-wide association studies.The strongest predictors included sex, CFTR severity score, and several genetic variants including one annotated to PRSS1, which encodes cationic trypsinogen. The final model defined in the CGS shows excellent agreement when validated on the FGMS, and the risk classifier shows slightly better performance at predicting CFRD risk later in life in both studies.We demonstrated clinical utility by comparing CFRD prevalence rates between the top 10% of individuals with the highest risk and the bottom 10% with the lowest risk. A web-based application was developed to provide practitioners with patient-specific CFRD risk to guide CFRD monitoring and treatment.

Background Shortcomings of inhaled antibiotic treatments for Pseudomonas aeruginosa infection in patients with cystic fibrosis (CF) include poor drug penetration, inactivation by sputum, poor efficiency due to protective biofilm, and short residence in the lung. Methods Eligible patients with forced expiratory volume in 1 s (FEV1) ≥25% of predicted value at screening and CF with chronic P. aeruginosa infection were randomly assigned to receive 3 treatment cycles (28 days on, 28 days off) of amikacin liposome inhalation suspension (ALIS, 590 mg QD) or tobramycin inhalation solution (TIS, 300 mg BID). The primary endpoint was noninferiority of ALIS vs TIS in change from baseline to day 168 in FEV1 (per-protocol population). Secondary endpoints included change in respiratory symptoms by Cystic Fibrosis Questionnaire-Revised (CFQ-R). Results The study was conducted February 2012 to September 2013. ALIS was noninferior to TIS (95% CI, −4.95 to 2.34) for relative change in FEV1 (L) from baseline. The mean increases in CFQ-R score from baseline on the Respiratory Symptoms scale suggested clinically meaningful improvement in both arms at the end of treatment in cycle 1 and in the ALIS arm at the end of treatment in cycles 2 and 3; however, the changes were not statistically significant between the 2 treatment arms. Treatment-emergent adverse events (TEAEs) were reported in most patients (ALIS, 84.5%; TIS, 78.8%). Serious TEAEs occurred in 17.6% and 19.9% of patients, respectively; most were hospitalisations for infective pulmonary exacerbation of CF. Conclusions Cyclical dosing of once-daily ALIS was noninferior to cyclical twice-daily TIS in improving lung function. ClinicalTrials.gov Identifier: NCT01315678

Bone mineral density (BMD) of the lumbar spine (L-spine) has been reported to be normal or increased in persons with chronic spinal cord injury (SCI).To determine BMD of the L-spine by dual-energy X-ray absorptiometry (DXA) and quantitative computerized tomography (qCT) in men with chronic SCI compared with able-bodied controls.Cross-sectional, comparative study.Clinical research unit, Veterans Affairs Medical Center, Bronx, NY, USA and Kessler Institute of Rehabilitation, West Orange, NJ, USA.Measurements of the L-spine were made in 20 men with SCI and compared with 15 able-bodied controls. The DXA images were acquired on a GE Lunar DPX-IQ. The qCT images of the L-spine were acquired on a Picker Q series computerized tomographic scanner.The mean ages for the SCI and control groups were 44+/-13 vs 42+/-9 years, and the duration of injury of the group with SCI was 14+/-11 years. There were no significant differences between the SCI and control groups for L-spine DXA BMD (1.391+/-0.210 vs 1.315+/-0.178 g/m(2)) or for L-spine DXA T-score (1.471+/-1.794 vs 0.782+/-1.481). L-spine qCT BMD was significantly lower in the SCI compared with the control group (1.296+/-0.416 vs 1.572+/-0.382 g/m(2), P=0.05); the T-score approached significance (-1.838+/-1.366 vs -0.963+/-1.227, P=0.059). Subjects with moderate degenerative joint disease (DJD) had significantly higher T-scores by DXA than those without or with mild DJD.Individuals with SCI who have moderate to severe DJD may have bone loss of the L-spine that may be underestimated by DXA, reducing awareness of the risk of fracture.

An increased prevalence of vitamin D deficiency has been reported in persons with chronic spinal cord injury (SCI), but treatment guidelines for replacement are not available. The purpose of this study was to evaluate two types of vitamin D therapy on calcium metabolism and vitamin D status in persons with SCI.Ten subjects with chronic SCI who were vitamin D deficient received 25 hydroxyvitamin D3 [25(OH)D], 50 microg twice a week, for 14 days (Study 1). Regardless of vitamin D status, 40 subjects received vitamin D3 800 IU (20 microg) daily for 12 months (Study 2). Supplemental calcium was administered. The response to therapy was determined by the effect upon serum 25(OH)D levels. Results are expressed as mean +/- standard deviation.In Study 1, serum 25(OH)D levels increased by day 14 (8.7 +/- 2.1 vs 14.7 +/- 3.6 ng/mL; P0.0005). However, in 8 of 10 subjects, 25(OH)D levels were still below the absolute lower limit of normal. Serum calcium levels were not significantly different, but urinary calcium excretion increased (103 +/- 81 vs 184 +/- 145 mg/d; P0.01). Serum parathyroid hormone (PTH) levels decreased (35 +/- 26 vs 1 7 +/- 12 pg/ mL; P0.01). In Study 2, after 12 months of vitamin D supplementation, 9 subjects had an absolute and 23 had a relative vitamin D deficiency, compared with 33 and 6 subjects, respectively, at baseline. By 12 months, the 25(OH)D level increased (10.7 +/- 7.1 to 22.5 +/- 7.5 ng/mL; P0.0001) and the serum PTH level decreased (37 +/- 16 vs 25 +/- 11 pg/mL; P0.0001).Although 25(OH)D levels significantly increased in both studies, the replacement therapies employed were not sufficient to recommend for adoption for clinical use, indicating the need for higher doses and/or for longer periods of administration.

Findings are presented from a cohort program between a university and local school districts to prepare special-education personnel. Participants (N=164), who were from 15 different cohorts, responded to an online survey. Follow-up face-to-face interviews were conducted with a representative sample of 29 participants. Perceived benefits included improved social-emotional and academic support; improved pedagogical skills, including academic and behavioral strategies, collaboration, and feeling more acculturated to the school climate; and improved logistical and financial supports. Implications for use of cohorts in the preparation of special-education personnel are discussed.

Some people with chronic spinal cord injury (SCI) have low vitamin D levels and secondary hyperparathyroidism.To determine whether, and to what extent, an acute calcium infusion decreased levels of N-telopeptide (NTx), a marker of osteoclastic activity, in individuals with chronic SCI.Case series.Eight men with chronic SCI. A relatively low serum 25 hydroxyvitamin D concentration (25[OH]Dor =20 ng/mL) and/or a high parathyroid hormone (PTH) (55 pg/mL) was a prerequisite for study inclusion.Calcium gluconate bolus 0.025 mmol elemental calcium/kg over 20 minutes followed by a constant infusion of 0.025 mmol/kg per hour for 6 hours was infused; blood samples were collected every 2 hours for measurement of serum total calcium, creatinine, NTx, and PTH.All results are expressed as means (+/- SDs). Baseline serum 25-hydroxyvitamin D level was 14.5 +/- 3.5 ng/mL (range: 10.2-19.6 ng/mL); PTH, 70 +/- 25 pg/mL (range: 37-100 pg/mL); and NTx, 21 +/- 7 nM bone collagen equivalents (BCE) (range: 14-34 nM). At 2, 4, and 6 hours after the calcium infusion, serum calcium rose from 9.3 +/- 0.2 to 10.8 +/- 0.9, 10.5 +/- 0.8, and 10.6 +/- 0.6 mg/d; PTH was suppressed from 70 +/- 25 pg/mL to 18 +/- 12, 16 +/- 9, and 15 +/- 9 pg/mL, respectively; NTx fell from 21 +/- 8 nM BCE to 17 +/- 5, 12 +/- 4, and 12 +/- 3 nM BCE, respectively.Serum NTx is a marker for bone collagen catabolism, and its reduction suggests that bone turnover was decreased. A relative deficiency of vitamin D associated with chronically elevated levels of PTH would be expected to increase bone turnover and to worsen the bone loss associated with immobilization.

This chapter reviews findings from the literature on the use of cohort programs in personnel preparation programs. Twenty-four investigations examining cohorts in higher education were identified: fourteen studies examined elementary, middle, or secondary education programs; seven studies described special education programs; and three described educational leadership cohort programs. Findings support the use of cohorts across special education, general education, and educational leadership personnel preparation programs. Reported positive benefits included social-emotional support, improved collaboration, communication, academic support, and reduced attrition. However, several studies also revealed unintended negative consequences. Such unintended consequences included negative interpersonal conflicts, development of cliques, and conflicts between students and faculty. Findings are discussed for future research and practice.

A randomized, placebo-controlled trial was per- formed to determine the effect of a vitamin D analog (1-alpha- hydroxyvitamin D 2 (1-alpha D 2 )) on the bone mineral density (BMD) in patients with chronic spinal cord injury (SCI). Forty subjects with chronic complete motor SCI were enrolled. The mean plus or minus standard deviation age and duration of injury were 42 plus or minus 12 yr and 11 plus or minus 10 yr, respectively. Either 4 micrograms 1-alpha D 2 (n = 19) or pla- cebo (n = 21) was administered daily for 24 mo. Metabolic markers of bone resorption and formation were obtained. Regional lower-limb dual-energy x-ray absorptiometry was performed at baseline and at 6, 12, 18, and 24 mo. Leg BMD and percent change from baseline significantly increased at 6 (percent change only), 12, 18, and 24 mo in the treatment group, but not in the placebo group. Urinary N-telopeptide, a marker of bone resorption, was significantly reduced during treatment with 1-alpha D 2 , but markers of bone formation were not changed.

Eleven subjects participated in a prospective placebo-controlled trial to address the efficacy of pamidronate in reducing bone loss in persons with acute spinal cord injury (SCI). We administered pamidronate (treatment) or normal saline (placebo) intravenously at baseline (22 to 65 days after injury) and sequentially over 12 months, with follow-up at 18 and 24 months. Regional bone mineral density (BMD) was lost over time, regardless of group. In the treatment group compared with the placebo group, we noted a mild early reduction in loss of total leg BMD. Significant bone loss from baseline occurred earlier in the placebo group at the regional sites than in the treatment group. However, by the end of the treatment and follow-up phases, both groups demonstrated a similar percent bone loss from baseline. Despite an early reduction in bone loss, pamidronate failed to prevent major, long-term bone loss in persons with acute neurologically complete SCI.