Use of Diabetes Technologies and Retinopathy in Adults With Type 1 Diabetes.

Liu TYA ，Shpigel J ，Khan F ，Smith K ，Prichett L ，Channa R ，Kanbour S ，Jones M ，Abusamaan MS ，Sidhaye A ，Mathioudakis N ，Wolf RM ... -  《JAMA Network Open》

Comparison of Two Modern Survival Prediction Tools, SORG-MLA and METSSS, in Patients With Symptomatic Long-bone Metastases Who Underwent Local Treatment With Surgery Followed by Radiotherapy and With Radiotherapy Alone.

Survival estimation for patients with symptomatic skeletal metastases ideally should be made before a type of local treatment has already been determined. Currently available survival prediction tools, however, were generated using data from patients treated either operatively or with local radiation alone, raising concerns about whether they would generalize well to all patients presenting for assessment. The Skeletal Oncology Research Group machine-learning algorithm (SORG-MLA), trained with institution-based data of surgically treated patients, and the Metastases location, Elderly, Tumor primary, Sex, Sickness/comorbidity, and Site of radiotherapy model (METSSS), trained with registry-based data of patients treated with radiotherapy alone, are two of the most recently developed survival prediction models, but they have not been tested on patients whose local treatment strategy is not yet decided. (1) Which of these two survival prediction models performed better in a mixed cohort made up both of patients who received local treatment with surgery followed by radiotherapy and who had radiation alone for symptomatic bone metastases? (2) Which model performed better among patients whose local treatment consisted of only palliative radiotherapy? (3) Are laboratory values used by SORG-MLA, which are not included in METSSS, independently associated with survival after controlling for predictions made by METSSS? Between 2010 and 2018, we provided local treatment for 2113 adult patients with skeletal metastases in the extremities at an urban tertiary referral academic medical center using one of two strategies: (1) surgery followed by postoperative radiotherapy or (2) palliative radiotherapy alone. Every patient's survivorship status was ascertained either by their medical records or the national death registry from the Taiwanese National Health Insurance Administration. After applying a priori designated exclusion criteria, 91% (1920) were analyzed here. Among them, 48% (920) of the patients were female, and the median (IQR) age was 62 years (53 to 70 years). Lung was the most common primary tumor site (41% [782]), and 59% (1128) of patients had other skeletal metastases in addition to the treated lesion(s). In general, the indications for surgery were the presence of a complete pathologic fracture or an impending pathologic fracture, defined as having a Mirels score of ≥ 9, in patients with an American Society of Anesthesiologists (ASA) classification of less than or equal to IV and who were considered fit for surgery. The indications for radiotherapy were relief of pain, local tumor control, prevention of skeletal-related events, and any combination of the above. In all, 84% (1610) of the patients received palliative radiotherapy alone as local treatment for the target lesion(s), and 16% (310) underwent surgery followed by postoperative radiotherapy. Neither METSSS nor SORG-MLA was used at the point of care to aid clinical decision-making during the treatment period. Survival was retrospectively estimated by these two models to test their potential for providing survival probabilities. We first compared SORG to METSSS in the entire population. Then, we repeated the comparison in patients who received local treatment with palliative radiation alone. We assessed model performance by area under the receiver operating characteristic curve (AUROC), calibration analysis, Brier score, and decision curve analysis (DCA). The AUROC measures discrimination, which is the ability to distinguish patients with the event of interest (such as death at a particular time point) from those without. AUROC typically ranges from 0.5 to 1.0, with 0.5 indicating random guessing and 1.0 a perfect prediction, and in general, an AUROC of ≥ 0.7 indicates adequate discrimination for clinical use. Calibration refers to the agreement between the predicted outcomes (in this case, survival probabilities) and the actual outcomes, with a perfect calibration curve having an intercept of 0 and a slope of 1. A positive intercept indicates that the actual survival is generally underestimated by the prediction model, and a negative intercept suggests the opposite (overestimation). When comparing models, an intercept closer to 0 typically indicates better calibration. Calibration can also be summarized as log(O:E), the logarithm scale of the ratio of observed (O) to expected (E) survivors. A log(O:E) > 0 signals an underestimation (the observed survival is greater than the predicted survival); and a log(O:E) < 0 indicates the opposite (the observed survival is lower than the predicted survival). A model with a log(O:E) closer to 0 is generally considered better calibrated. The Brier score is the mean squared difference between the model predictions and the observed outcomes, and it ranges from 0 (best prediction) to 1 (worst prediction). The Brier score captures both discrimination and calibration, and it is considered a measure of overall model performance. In Brier score analysis, the "null model" assigns a predicted probability equal to the prevalence of the outcome and represents a model that adds no new information. A prediction model should achieve a Brier score at least lower than the null-model Brier score to be considered as useful. The DCA was developed as a method to determine whether using a model to inform treatment decisions would do more good than harm. It plots the net benefit of making decisions based on the model's predictions across all possible risk thresholds (or cost-to-benefit ratios) in relation to the two default strategies of treating all or no patients. The care provider can decide on an acceptable risk threshold for the proposed treatment in an individual and assess the corresponding net benefit to determine whether consulting with the model is superior to adopting the default strategies. Finally, we examined whether laboratory data, which were not included in the METSSS model, would have been independently associated with survival after controlling for the METSSS model's predictions by using the multivariable logistic and Cox proportional hazards regression analyses. Between the two models, only SORG-MLA achieved adequate discrimination (an AUROC of > 0.7) in the entire cohort (of patients treated operatively or with radiation alone) and in the subgroup of patients treated with palliative radiotherapy alone. SORG-MLA outperformed METSSS by a wide margin on discrimination, calibration, and Brier score analyses in not only the entire cohort but also the subgroup of patients whose local treatment consisted of radiotherapy alone. In both the entire cohort and the subgroup, DCA demonstrated that SORG-MLA provided more net benefit compared with the two default strategies (of treating all or no patients) and compared with METSSS when risk thresholds ranged from 0.2 to 0.9 at both 90 days and 1 year, indicating that using SORG-MLA as a decision-making aid was beneficial when a patient's individualized risk threshold for opting for treatment was 0.2 to 0.9. Higher albumin, lower alkaline phosphatase, lower calcium, higher hemoglobin, lower international normalized ratio, higher lymphocytes, lower neutrophils, lower neutrophil-to-lymphocyte ratio, lower platelet-to-lymphocyte ratio, higher sodium, and lower white blood cells were independently associated with better 1-year and overall survival after adjusting for the predictions made by METSSS. Based on these discoveries, clinicians might choose to consult SORG-MLA instead of METSSS for survival estimation in patients with long-bone metastases presenting for evaluation of local treatment. Basing a treatment decision on the predictions of SORG-MLA could be beneficial when a patient's individualized risk threshold for opting to undergo a particular treatment strategy ranged from 0.2 to 0.9. Future studies might investigate relevant laboratory items when constructing or refining a survival estimation model because these data demonstrated prognostic value independent of the predictions of the METSSS model, and future studies might also seek to keep these models up to date using data from diverse, contemporary patients undergoing both modern operative and nonoperative treatments. Level III, diagnostic study.

Lee CC ，Chen CW ，Yen HK ，Lin YP ，Lai CY ，Wang JL ，Groot OQ ，Janssen SJ ，Schwab JH ，Hsu FM ，Lin WH ... -  《-》

Hybrid closed-loop systems for managing blood glucose levels in type 1 diabetes: a systematic review and economic modelling.

Asgharzadeh A ，Patel M ，Connock M ，Damery S ，Ghosh I ，Jordan M ，Freeman K ，Brown A ，Court R ，Baldwin S ，Ogunlayi F ，Stinton C ，Cummins E ，Al-Khudairy L ... -  《-》

Anti-vascular endothelial growth factors in combination with vitrectomy for complications of proliferative diabetic retinopathy.

Vitrectomy is an established treatment for the complications of proliferative diabetic retinopathy (PDR). However, a number of complications can occur during and after vitrectomy for PDR. These include bleeding and the creation of retinal holes during surgery, and bleeding, retinal detachment and scar tissue on the retina after surgery. These complications can limit vision, require further surgery and delay recovery. The use of anti-vascular endothelial growth factor (anti-VEGF) agents injected into the eye before surgery has been proposed to reduce the occurrence of these complications. Anti-VEGF agents can reduce the amount and vascularity of abnormal new vessels associated with PDR, facilitating their dissection during surgery, reducing intra- and postoperative bleeding, and potentially improving outcomes. To assess the effects of perioperative anti-VEGF use on the outcomes of vitrectomy for the treatment of complications for proliferative diabetic retinopathy (PDR). We searched the Cochrane Central Register of Controlled Trials (CENTRAL; which contains the Cochrane Eyes and Vision Trials Register; 2022, Issue 6); Ovid MEDLINE; Ovid Embase; the ISRCTN registry; ClinicalTrials.gov and the WHO ICTRP. The date of the search was 22 June 2022. We included randomised controlled trials (RCTs) that looked at the use of anti-VEGFs and the incidence of complications in people undergoing vitrectomy for PDR.   DATA COLLECTION AND ANALYSIS: Two review authors independently assessed and extracted the data. We used the standard methodological procedures expected by Cochrane. The critical outcomes of the review were the mean difference in best corrected visual acuity (BCVA) between study arms at six (± three) months after the primary vitrectomy, the incidence of early postoperative vitreous cavity haemorrhage (POVCH, within four weeks postoperatively), the incidence of late POVCH (occurring more than four weeks postoperatively), the incidence of revision surgery for POVCH within six months, the incidence of revision surgery for recurrent traction/macular pucker of any type and/or rhegmatogenous retinal detachment within six months and vision-related quality of life (VRQOL) measures. Important outcomes included the proportion of people with a visual acuity of counting fingers (1.8 logMAR or worse), the number of operative retinal breaks reported and the frequency of silicone oil tamponade required at time of surgery. The current review includes 28 RCTs that looked at the pre- or intraoperative use of intravitreal anti-VEGFs to improve the outcomes of pars plana vitrectomy for complications of PDR. The studies were conducted in a variety of countries (11 from China, three from Iran, two from Italy, two from Mexico and the remaining studies from South Korea, the UK, Egypt, Brazil, Japan, Canada, the USA, Indonesia and Pakistan). The inclusion criteria for entry into the studies were the well-recognised complications of proliferative retinopathy: non-clearing vitreous haemorrhage, tractional retinal detachment involving the macula or combined tractional rhegmatogenous detachment. The included studies randomised a total of 1914 eyes.  We identified methodological issues in all of the included studies. Risk of bias was highest for masking of participants and investigators, and a number of studies were unclear when describing randomisation methods and sequence allocation. Participants receiving intravitreal anti-VEGF in addition to pars plana vitrectomy achieved better BCVA at six months compared to people undergoing vitrectomy alone (mean difference (MD) -0.25 logMAR, 95% confidence interval (CI) -0.39 to -0.11; 13 studies, 699 eyes; low-certainty evidence). Pre- or intraoperative anti-VEGF reduced the incidence of early POVCH (12% versus 31%, risk ratio (RR) 0.44, 95% CI 0.34 to 0.58; 14 studies, 1038 eyes; moderate-certainty evidence). Perioperative anti-VEGF use was also associated with a reduction in the incidence of late POVCH (10% versus 23%, RR 0.47, 95% CI 0.30 to 0.74; 11 studies, 579 eyes; high-certainty evidence). The need for revision surgery for POVCH occurred less frequently in the anti-VEGF group compared with control, but the confidence intervals were wide and compatible with no effect (4% versus 13%, RR 0.44, 95% CI 0.15 to 1.28; 4 studies 207 eyes; moderate-certainty evidence). Similar imprecisely measured effects were seen for revision surgery for rhegmatogenous retinal detachment (5% versus 11%, RR 0.50, 95% CI 0.15 to 1.66; 4 studies, 145 eyes; low-certainty evidence).  Anti-VEGFs reduce the incidence of intraoperative retinal breaks (12% versus 31%, RR 0.37, 95% CI 0.24 to 0.59; 12 studies, 915 eyes; high-certainty evidence) and the need for silicone oil (19% versus 41%, RR 0.46, 95% CI 0.27 to 0.80; 10 studies, 591 eyes; very low-certainty evidence). No data were available on quality of life outcomes or the proportion of participants with visual acuity of counting fingers or worse. The perioperative use of anti-VEGF reduces the risk of late POVCH, probably results in lower early POVCH risk and may improve visual outcomes. It also reduces the incidence of intraoperative retinal breaks. The evidence is very uncertain about its effect on the need for silicone oil tamponade. The reported complications from its use appear to be low. Agreement on variables included and outcome standardisation is required in trials studying vitrectomy for PDR.

Dervenis P ，Dervenis N ，Smith JM ，Steel DH ... -  《Cochrane Database of Systematic Reviews》

Cervical mucus patterns and the fertile window in women without known subfertility: a pooled analysis of three cohorts.

What is the normal range of cervical mucus patterns and number of days with high or moderate day-specific probability of pregnancy (if intercourse occurs on a specific day) based on cervical mucus secretion, in women without known subfertility, and how are these patterns related to parity and age? The mean days of peak type (estrogenic) mucus per cycle was 6.4, the mean number of potentially fertile days was 12.1; parous versus nulliparous, and younger nulliparous (<30 years) versus older nulliparous women had more days of peak type mucus, and more potentially fertile days in each cycle. The rise in estrogen prior to ovulation supports the secretion of increasing quantity and estrogenic quality of cervical mucus, and the subsequent rise in progesterone after ovulation causes an abrupt decrease in mucus secretion. Cervical mucus secretion on each day correlates highly with the probability of pregnancy if intercourse occurs on that day, and overall cervical mucus quality for the cycle correlates with cycle fecundability. No prior studies have described parity and age jointly in relation to cervical mucus patterns. This study is a secondary data analysis, combining data from three cohorts of women: 'Creighton Model MultiCenter Fecundability Study' (CMFS: retrospective cohort, 1990-1996), 'Time to Pregnancy in Normal Fertility' (TTP: randomized trial, 2003-2006), and 'Creighton Model Effectiveness, Intentions, and Behaviors Assessment' (CEIBA: prospective cohort, 2009-2013). We evaluated cervical mucus patterns and estimated fertile window in 2488 ovulatory cycles of 528 women, followed for up to 1 year. Participants were US or Canadian women age 18-40 years, not pregnant, and without any known subfertility. Women were trained to use a standardized protocol (the Creighton Model) for daily vulvar observation, description, and recording of cervical mucus. The mucus peak day (the last day of estrogenic quality mucus) was used as the estimated day of ovulation. We conducted dichotomous stratified analyses for cervical mucus patterns by age, parity, race, recent oral contraceptive use (within 60 days), partial breast feeding, alcohol, and smoking. Focusing on the clinical characteristics most correlated to cervical mucus patterns, linear mixed models were used to assess continuous cervical mucus parameters and generalized linear models using Poisson regression with robust variance were used to assess dichotomous outcomes, stratifying by women's parity and age, while adjusting for recent oral contraceptive use and breast feeding. The majority of women were <30 years of age (75.4%) (median 27; IQR 24-29), non-Hispanic white (88.1%), with high socioeconomic indicators, and nulliparous (70.8%). The mean (SD) days of estrogenic (peak type) mucus per cycle (a conservative indicator of the fertile window) was 6.4 (4.2) days (median 6; IQR 4-8). The mean (SD) number of any potentially fertile days (a broader clinical indicator of the fertile window) was 12.1 (5.4) days (median 11; IQR 9-14). Taking into account recent oral contraceptive use and breastfeeding, nulliparous women age ≥30 years compared to nulliparous women age <30 years had fewer mean days of peak type mucus per cycle (5.3 versus 6.4 days, P = 0.02), and fewer potentially fertile days (11.8 versus 13.9 days, P < 0.01). Compared to nulliparous women age <30 years, the likelihood of cycles with peak type mucus ≤2 days, potentially fertile days ≤9, and cervical mucus cycle score (for estrogenic quality of mucus) ≤5.0 were significantly higher among nulliparous women age ≥30 years, 1.90 (95% confidence interval (CI) 1.18, 3.06); 1.46 (95% CI 1.12, 1.91); and 1.45 (95% CI 1.03, 2.05), respectively. Between parous women, there was little difference in mucus parameters by age. Thresholds set a priori for within-woman variability of cervical mucus parameters by cycle were examined as follows: most minus fewest days of peak type mucus >3 days (exceeded by 72% of women), most minus fewest days of non-peak type mucus >4 days (exceeded by 54% of women), greatest minus least cervical mucus cycle score >4.0 (exceeded by 73% of women), and most minus fewest potentially fertile days >8 days (found in 50% of women). Race did not have any association with cervical mucus parameters. Recent oral contraceptive use was associated with reduced cervical mucus cycle score and partial breast feeding was associated with a higher number of days of mucus (both peak type and non-peak type), consistent with prior research. Among the women for whom data were available (CEIBA and TTP), alcohol and tobacco use had minimal impact on cervical mucus parameters. We did not have data on some factors that may impact ovulation, hormone levels, and mucus secretion, such as physical activity and body mass index. We cannot exclude the possibility that some women had unknown subfertility or undiagnosed gynecologic disorders. Only 27 women were age 35 or older. Our study participants were geographically dispersed but relatively homogeneous with regard to race, ethnicity, income, and educational level, which may limit the generalizability of the findings. Patterns of cervical mucus secretion observed by women are an indicator of fecundity and the fertile window that are consistent with the known associations of age and parity with fecundity. The number of potentially fertile days (12 days) is likely greater than commonly assumed, while the number of days of highly estrogenic mucus (and higher probability of pregnancy) correlates with prior identifications of the fertile window (6 days). There may be substantial variability in fecundability between cycles for the same woman. Future work can use cervical mucus secretion as an indicator of fecundity and should investigate the distribution of similar cycle parameters in women with various reproductive or gynecologic pathologies. Funding for the three cohorts analyzed was provided by the Robert Wood Johnson Foundation (CMFS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (TTP), and the Office of Family Planning, Office of Population Affairs, Health and Human Services (CEIBA). The authors declare that they have no conflict of interest. N/A.

Najmabadi S ，Schliep KC ，Simonsen SE ，Porucznik CA ，Egger MJ ，Stanford JB ... -  《-》