Aim: Low back pain affects many people at some point in their life. Whenever pharmacologic and other conservative treatments of chronic pain fail, ablative and interventional methods are attempted on the assumption that interrupting nerve conduction prevents central pain cognition. Pulsed radiofrequency using multifunctional epidural electrodes can be used for multiple etiologies of chronic low back and leg pain with a low complication rate and minimal side effects.Methods: The records of the 188 patients who underwent pulsed radiofrequency with multifunctional epidural electrode between October 2014 and March 2017 in Algology clinic were examined retrospectively. Visual analogue scale (VAS) for pain, response to straight leg raising test (SLR), lumbar range of motion, analgesic use, patient satisfaction score, need for open operation or other interventional procedure were collected.Results: VAS and SLR tests were found to be significantly improved compared with the preoperative values. The VAS scores at the 10th day and first, third and sixth months were significantly decreased compared to baseline scores (p<0.001). Also, SLR tests were significantly improved compared to baseline scores at the same intervals (p<0.001).Conclusion: Pulsed radiofrequency with multifunctional epidural electrode is a safe and effective method for low back pain which is caused by several pathologies. Low back pain is a condition that affects many people in a certain period of their lives. Most of the patients (> 85%) applying to primary care due to low back pain have non-specific low back pain, in other words, the underlying cause of their low back pain cannot be defined precisely ,2.Low back pain has the highest prevalence in people aged from 40 to 80 years and it has been observed that the prevalence of chronic low back pain has changed over the years due to the change in lifestyles and technology. Two studies have shown that the prevalence of chronic low back pain has doubled over time ,4. This The cause of low back pain is mostly non-specific . The leaPrimary care for the treatment of low back pain includes non-invasive treatment and non-drug methods, such as patient education and suggestions on active life and exercise . NeverthApplying epidural or transforaminal corticosteroid injections and dorsal root ganglion (DRG) radiofrequency ablation are invasive treatment options in cases where conservative treatments are insufficient . The fleFollowing the Ethics Committee of Uludag University Faculty of Medicine approval (2017-17/45), the study was performed as the retrospective analysis of the medical files of patients admitted to the Clinics of the Algology Department and underwent pulsed radiofrequency (PRF) with multifunctional epidural electrode between October 2014 and March 2017. Patients who had low back pain with unilateral/bilateral radicular pain due to various aetiologies, who had no improvement of pain despite medical treatment and other standard treatment methods, and who were regarded as Class I-III according to the American Society of Anaesthesiologists (ASA) classification were included in the study. We investigated post-procedure Visual Analogue Scale (VAS) scores, response to straight leg raise (SLR) test, range of motion (ROM) of the lumbar joints, use of analgesics, and patient satisfaction level, and whether the patient had any operation or invasive procedure after PRF with multifunctional epidural electrode.Data of 188 patients meeting the inclusion criteria were examined. Thirty-six patients who did not show up for the post-procedure follow-up visit or whose data could not be accessed were excluded from the study. As a result, the data of 152 patients were evaluated within the scope of the study.Age, gender, BMI, ASA class, comorbidities and pain duration were recorded for each patient. If they had a history of surgery or neuropathic complaints were also recorded. The patients’ VAS scores before the procedure and after the procedure and at the post-procedural 10th day and first, third and sixth months, response to straight leg raise test before and after the procedure, analgesic use before and after the procedure, and the range of motion values measured before and after the procedure were recorded. After the procedure, patient satisfaction was recorded on a 0-4 scale . In our study, the range of motion was measured with a goniometer, and the straight leg raise test was performed as described above and the results were recorded in angles.Normal distribution of variables was assessed using the Shapiro-Wilk test. Continuous variables are expressed with the median (minimum-maximum) and average±standard deviation values. Categorical variables are expressed as % (n=). The dependent paired samples Wilcoxon test was used for comparisons between the groups generated according to the results of the normal distribution tests. Statistical Package for Social Sciences (SPSS) version 21  was used for statistical analyses. p<0.05 was considered statistically significant.Pulsed radiofrequency application with multifunctional epidural electrode (PASHA electrode)After establishing peripheral vascular access, we apply electrocardiography (ECG), pulse-oximetry (SpO2) and non-invasive blood pressure monitoring for patients in accordance with the recommendations of ASA. Patients are placed in the prone position and a neutral electrode is located on the appropriate site. The intervention site is sterilized with antiseptic solution and covered. Sterile conditions are maintained during the procedure. Sacral hiatus is identified, and 3 ml of 2% prilocaine solution is applied to the subcutaneous and deep tissues as the local anaesthetic. Epidural space is accessed using a 14-gauge introducer cannula. Radiopaque material is injected through the cannula and its location is confirmed with fluoroscopy. The multifunctional electrode is advanced through the cannula and placed at the targeted spinal level, dorsal column of medulla spinals or cauda equina nerves, according to MRI, in the craniolateral direction. Its location is checked with anteroposterior, oblique and lateral fluoroscopic images. The proximal end of the catheter is attached to the radiofrequency generator in a sterile way. After observing proper placement, stimulation is applied at 0.8 V, 50 HZ sensory stim, and the location of the catheter is confirmed when patients feel a stimulation in their symptom area; the point of application is determined. PRF is applied at 42 °C for 240-360 seconds with an active phase of 20 milliseconds and a silent period of 480 milliseconds. After the application, the catheter is withdrawn. Patients are followed up for four to six hours for a loss in motor function, sensation and other complications. On the follow-up visit, patients’ VAS scores, SLR test results, joint range of motion, and satisfaction levels are recorded.Demographic data and distribution of ASA scores of 152 patients are shown in Table Most common diagnoses in patients receiving pulsed radiofrequency with multifunctional epidural electrode were respectively lumbar disc herniation (LDH) , spinal stenosis , and spondylolisthesis plus spinal stenosis .The median VAS score of 152 patients examined in the study before treatment was 6 (4:10) (average±standard deviation: 6.59±0.99). The VAS scores evaluated on day 10 and months one, three, and six after treatment were significantly lower as compared to the VAS values obtained before treatment  Table . In the study, the Wilcoxon test was used to compare the pre-treatment VAS values with the VAS values measured 10 days and one, three, and six months after treatment Table . The preWe compared the pre-treatment straight leg raise test values with the post-treatment straight leg raise test values according to diagnosis. In the patients with LDH, the post-treatment SLR values were found to be significantly higher than the pre-treatment SLR values (p<0.001). In the patients with spinal stenosis, the post-treatment SLR values were also significantly higher compared to the pre-treatment SLR values (p<0.001). furthermore, the post-treatment SLR values of patients with spondylolisthesis plus spinal stenosis were also found to be significantly higher compared to the pre-treatment SLR values (p=0.083).We compared the pre-treatment range of motion for joint flexion with the post-treatment range of motion by diagnosis. In the group diagnosed with LDH, the post-treatment flexion ROM was found to be significantly increased compared to pre-treatment (p=0.003). In the group of patients with spinal stenosis, no significant difference was found between pre-treatment and post-treatment ROM values in flexion (p=0.102). Similarly, there was no significant difference between pre-treatment and post-treatment ROM values for flexion in patients with spondylolisthesis plus spinal stenosis (p=0.157).We compared the pre-treatment range of motion for joint extension with the post-treatment range of motion by diagnosis. In the patients with LDH, the post-treatment ROM values for extension were found to be significantly higher as compared to the pre-treatment ROM values (p<0.001). On the other hand, no significant difference was found between pre-treatment and post-treatment extension ROM values in the group diagnosed with spinal stenosis (p=0.066). There was no significant difference between pre-treatment and post-treatment ROM values for flexion in the group with spondylolisthesis plus spinal stenosis (p=0.059).We made a comparison between the pre-treatment range of motion for lateral flexion and the post-treatment range of motion for lateral flexion according to patients’ diagnoses. In the group diagnosed with LDH, the post-treatment ROM values for lateral flexion were found to be significantly higher than the pre-treatment ROM values (p<0.002). Nevertheless, there was no significant difference between pre-treatment and post-treatment lateral flexion ROM values in the group diagnosed with spinal stenosis (p=0.046). There was no significant difference between pre-treatment and post-treatment ROM values for lateral flexion in the group with spondylolisthesis plus spinal stenosis (p=0.157).Whereas 113 patients (74.3%) were using analgesic before treatment, this was decreased to 83 patients (54.6%) after the procedure. It was observed that the number of patients undergoing a physiotherapy protocol was 58 (38.2%) before treatment and it decreased to 11 (7.2%) after treatment. The number of patients who received interventional treatment by algology physicians before the application of pulsed radiofrequency with multifunctional epidural electrode was 65 (42%), and 87 (57%) did not have any history of surgery.There were 42 patients 27.6%) with a history of surgery before treatment, whereas 24 patients (15.8%) underwent surgery after treatment. When the patients who had history of surgery before the treatment were examined, it was observed that the VAS scores prior to the application of the pulsed radiofrequency with multifunctional epidural electrode were significantly higher than the VAS scores recorded on the 10th day and in the 1st, 3rd and 6 months after the treatment . Moreover, when the patients who did not have history of surgery before the treatment were examined, the VAS scores prior to the application of the pulsed radiofrequency with multifunctional epidural electrode were also significantly higher than the VAS scores recorded on the 10th day and in the first, third and sixth months after the treatment  . Similarly, the post-treatment SLR values of the group without a history of surgery were significantly higher than the pre-treatment SLR values (p<0.001).Furthermore, the pre-treatment range of motion for flexion was compared with the post-treatment range of motion in patients with and without a surgical history prior to the application of pulsed radiofrequency with multifunctional epidural electrode. In the group with a history of surgery, the post-treatment ROM values for flexion were significantly higher compared to the pre-treatment values (p<0.034). In the group without a history of surgery, the post-treatment ROM values for flexion were significantly higher compared to the pre-treatment values (p=0.003).We also compared the pre-treatment range of motion for extension with the post-treatment range of motion in patients with and without a surgical history before the application of pulsed radiofrequency with multifunctional epidural electrode. There was no significant difference between pre-treatment and post-treatment extension ROM values in the group that had surgery prior to the treatment (p=0.066). On the other hand, the post-treatment ROM values for extension were significantly higher compared to the pre-treatment values in the group without a history of surgery (p<0.001).A comparison was also made between the pre-treatment and post-treatment range of motion levels for lateral flexion in patients with and without a surgical history prior to the application of pulsed radiofrequency with multifunctional epidural electrode. No significant difference was determined between the pre-treatment and post-treatment ROM values for lateral flexion in the group that had surgery prior to the treatment (p=0.083). In the group without a history of surgery, the post-treatment ROM values for lateral flexion were significantly increased compared to the pre-treatment values (p<0.001) Table .The number of patients that had neuropathic pain complaints before treatment was 58 (38.2%), and the number of patients whose pain had no neuropathic feature was 94 (61.8%). When the patients who had neuropathic pain were analysed, it was observed that their VAS scores prior to the application of the pulsed radiofrequency with multifunctional epidural electrode were significantly higher than the VAS scores measured 10 days and one, three and six months after the treatment . Moreover, patients who had low back pain without radicular leg pain were examined; the VAS scores prior to the application of the pulsed radiofrequency with multifunctional epidural electrode were significantly higher compared to the VAS scores on the 10th day and in the first, third and sixth months after the treatment .There were no complications in the 152 patients whose data we examined. None of the 152 patients developed neurological dysfunction after the procedure.Patient satisfaction score was 1 in 21 (13.8%), 2 in 26 (17.1%), 3 in 39 (25.7%), and 4 in 66 (43.4%) patients at six months after the procedure. There were no patients with a satisfaction score of zero.The mechanism of action of PRF in pain management is currently not clarified with certainty. According to general opinion, radiofrequency has neuromodulatory and anti-inflammatory effects. Microscopic damage is evaluated after exposure to radio waves, as observed in membrane abnormalities and mitochondrial morphology, as well as in interruption and disorganization of microfilaments and microtubules. This ultrastructural pathway occurs more widely in type C and type A nerve fibers. Immune cells are affected by radio waves and inhibit the production of pro-inflammatory cytokines, such as interleukin-1b and interleukin-6 (IL-6). Radiofrequency can induce changes in membranes and intracellular structures, consequently modifying the transmission of action potentials and perception of pain. PRF activates the descending noradrenergic and serotoninergic pain inhibition pathways as well as inhibits excitatory nociceptive C fibers. Microglial activity can be decreased by PRF intervention in DRG. Microglia can cause chronic neuropathic pain through the release of various cytokines and chemokines associated with the transmission of pain signals and also decreased microglial activity may prevent the development of chronic neuropathic pain . On the The patients included in the study were with or without history of surgery whose pain was not relieved with more conservative methods. Some of the patients had indications for surgery, but did not want to undergo surgery or had a high risk for surgery due to their medical condition. The VAS scores of the patients who underwent pulsed radiofrequency with multifunctional epidural electrode were significantly lower 10 days and one, three and six months after the procedure as compared to the pre-treatment values.The prevalence of chronic low back pain by age varies between studies, but it is three to four times more prevalent in the group over 50 years of age than in the group aged 18-30 years . SimilarIn our study, PRF application with multifunctional epidural electrode was most frequently applied to patients with diagnoses of lumbar disc herniation (n=92), spinal stenosis (n=47), and those with spondylolisthesis and spinal stenosis (n=13), respectively. Disc herniation is the most frequent cause of lumbar radicular syndrome in patients under 50 years. After the age of 50, radicular pain often occurs due to degenerative changes in the spine .Pulsed radiofrequency applied to the dorsal root ganglion (PRF-DRG) is an attractive alternative to epidural steroid injection in the treatment of chronic lumbar radicular pain. In pulsed radiofrequency, it is possible to perform target-specific applications and avoid the use of steroids, and thus, eliminate endocrine effects including adrenal suppression, water retention and glucose intolerance. It is known that the injection of steroids, and also of steroid particles, into the artery have potentially serious adverse effects including spinal cord infarction and death . There aMost of the studies investigating the effects of PRF have been conducted with the transforaminal approach. The multifunctional flexible electrode has advantages over rigid equipment, such as the ability to apply stimulation more closely to the DRG and to infuse drugs into the epidural space . Thanks It was observed when the patients were grouped by diagnosis that the VAS scores of the patients diagnosed with LDH were significantly lower 10 days and one, three and six months after the procedure compared to prior to the procedure. There are many studies indicating that the application of PRF to DRG is a safe procedure. Choi et al. reported that 71% of patients with chronic cervical radicular type pain resistant to repeat transforaminal epidural steroid injections (TFESIs) were satisfied with the effectiveness of PRF-DRG ,21. A prospective randomized trial conducted on patients with radicular pain due to a herniated disc made a comparison between PRF and transforaminal steroid injection, and the VAS scores for cervical and lumbar radicular pain were found to be significantly decreased at the 12th week following the treatments in both groups. There was no statistically significant difference between the PRF and TFESI groups in the VAS, Oswestry Disability Index (ODI) and Neck Disability Index (NDI) scores in any period of the follow-up. Applying PRF to dorsal root ganglion is as effective as TFESI in radicular pain caused by disc herniation, and it allows avoidance from the side effects of the steroids . Based oLumbosacral radicular pain is characterized by a radiating pain in one or more lumbar or sacral dermatomes, and it may or may not be accompanied by symptoms of function loss and other radicular irritation symptoms .A retrospective study investigated patients with radicular syndrome due to disc herniation, spinal stenosis and failed back surgery syndrome (FBSS) that underwent PRF, and reported a significant decrease in analgesic consumption in the groups with disc herniation and spinal stenosis. However, no significant decrease was reported in the analgesic consumption of patients with failed back surgery syndrome . Van BoxShanthanna et al. introduced the first randomized controlled study on the effects of PRF in the treatment of chronic radicular pain . The autIn the prospective randomized trial conducted by Ross et al. on 197 patients, who once underwent lumbar surgery, the epidural scarring caused by lumbar surgery was followed up with magnetic resonance imaging. It was observed in the comparison between epidural scarring and radicular pain that patients who had extensive epidural scarring were 3.2 times more likely to experience recurrent radicular pain . It was In this study, the pre-procedural analgesic use was 74.3% in all groups, but this rate decreased to 54.6% after the procedure. Cohen et al. showed that the application of PRF to the peripheral nerve is superior to conservative medical treatment in patients with thoracic segmental pain .In studies of PRF application with multifunctional epidural electrode, no major or minor complications have been reported, except for headache lasting for a maximum of one day after treatment . MoreoveThe greatest problem in the studies investigating PRF is that there is no standardization in PRF parameters, and the inclusion criteria and reports are heterogeneous . In two The major weakness of our study is that it is a retrospective study and does not include a control group. However, it provides valuable information on the efficacy and potential complications of the multifunctional epidural electrode, on which there is limited data in the literature.In conclusion, it has been demonstrated that pulsed radiofrequency procedure with multifunctional epidural electrode is an effective and safe method in the short- and medium-term for lumbar spinal pain reflected on the low back and legs.Low back pain is a condition that affects many people in a certain period of their lives. It has been observed that the prevalence of chronic low back pain has changed over the years due to the change in lifestyles and technology. Primary care for the treatment of low back pain includes non-invasive treatment and non-drug methods, such as patient education and suggestions on active life and exercise. Patients that have low back pain accompanied with severe and progressive loss of motor strength or signs of cauda equine should be immediately referred to surgery. Applying epidural or transforaminal corticosteroid injections and dorsal root ganglion (DRG) radiofrequency have become common next steps in care where conservative treatments are insufficient. In this study, patients, who had low back pain due to various aetiologies, who had no improvement of pain despite medical treatment and other standard treatment methods, were included in the study and it has been demonstrated that pulsed radiofrequency procedure with multifunctional epidural electrode is an effective and safe method in the short- and medium-term for lumbar spinal pain reflected on the low back and legs.


Pancreatic cancer is one of the most common malignancies worldwide. This study is aimed at searching the possible genetic mutations and the value of novel gene mutation in the DNA damage-inducible transcript 4 (DDIT4) and signaling pathway in pancreatic cancer. Polymerase chain reaction (PCR) was performed to amplify the DNA sequences of DDIT4 from patients with pancreatic ductal adenocarcinoma. In addition, we used IHC to detect the expression level of DDIT4 in patients with pancreatic cancer in different types of gene mutation. Double-labeled immunofluorescence was employed to explore the expression levels of DDIT4/LC3 and their potential correlation. Our work indicated the two novel stable gene mutations in DDIT4 mRNA 3′-untranslated region (m.990 U>A and m.1246 C>U). Thirteen samples were found to have mutation in the DDIT4 3′-untranslated regions (UTR). To further verify the influence of gene mutation on protein expression, we performed immunohistochemistry on different gene mutation types, and we found a correlation between DDIT4 expression and gene mutation, which is accompanied by nuclear staining deepening. In order to further discuss the clinical value of DDIT4 gene mutation, immunofluorescence suggested that the expression of DDIT4 colocated with LC3; thus, we speculated that DDIT4 mutation may be involved in autophagy in pancreatic cancer cell. In this study, we found mutation in the 3′-UTR region of DDIT4, which may be associated with DDIT4 expression and tumor autophagy in pancreatic cancer tissues. Pancreatic cancer ranked the fourth most common cause of fatalities due to cancer in America. The 5-year relative survival rate of patients with pancreatic cancer was only 9% . AccordiThe somatic and germline genetic mutation contributes to the occurrence of pancreatic cancer, and the special gene is a novel target to kill the cancer cell. Wood et al. summarized the 24 sporadic gene mutations including the common gene mutation  which is more than 20% prevalence . Gene muDNA damage-inducible transcript 4 (DDIT4) was induced by a variety of stress conditions, including oxidative stress , endoplaWe speculated that DDIT4 gene mutation may be involved in pancreatic cancer cell adapted to antitumor therapy and harsh microenvironment. Mechanistically, the gene mutation and expression level of DDIT4 may affect the formation of autophagosomes, which will contribute to the survival of PDAC.Patients with pancreatic neoplasm from the First Affiliated Hospital of Fujian Medical University were included between 2018 and 2019. The patients we included were set as the experimental group and the control group, respectively, according to the pathological results. The experimental group is the group of patients with pathologically confirmed PDAC diagnosis. The control group is the group of patients with pancreatic neoplasm without PDAC. The inclusion criteria are as follows. (1) The patients had complete clinical data and follow-up data. (2) The patients signed informed consent. Patients with any comorbid or previous malignancies were excluded from the study. The related information of patients with pancreatic cancer was collected including age, gender, TMN stage, surgical method, outcome, chemotherapy regimens, pathological grading, imaging features, and the level of tumor markers . This stPancreatic neoplasm tissue and adjacent healthy tissue samples were collected in liquid nitrogen and stored at -80°C. A TIANamp tissue DNA extraction kit  was used to extract and store DNA from pancreatic cancer tissues and control tissues. The full-length DDIT4 was amplified and underwent gel electrophoresis following purification. Multiple sequencing was performed and analyzed by Sangon Biotech Co., Ltd. The forward primer of PCR was 5′-GTTCGCACACCCATTCAA-3′, and the reverse one was 5′-GCATAGGTCTTAATACTTGAACAT-3′. The condition of PCR was initial denaturing step, and an ABI PRISM 7700 sequencer  was used for gene sequencing.Pancreatic tissues from patients with pancreatic cancer were used for hematoxylin and eosin staining and immunohistochemistry. DDIT4 antibodies were obtained from Arigo Biolaboratories . Eight-micrometer sections were made in all paraffin-embedded pancreatic tissue. The slides were immunolabeled with monoclonal antibodies against DDIT4 (DNA damage-inducible transcript 4). Immunohistochemistry was performed using an automated immunohistochemical stainer according to the manufacturer's guidelines. Substitution of the primary antibody with phosphate-buffered saline was used as a negative control.Pancreatic tissues from patients were fixed with 4% paraformaldehyde, and pathological section was made. The sections were permeabilized, and nonspecific binding was blocked. Primary monoclonal antibodies specific for LC3 and DDIT4 were incubated and secondary antibodies were applied for 2 hours at room temperature, and the nucleus was stained with DAPI. The stained samples were photographed with a fluorescence inverted microscope in half an hour. Our immunofluorescence imaging uses the same exposure time.U test for two groups and Kruskal-Wallis test for more than two groups. Spearman's rank correlation coefficient estimated the degree of association between two variables. Significance was calculated at P < 0.05 by GraphPad Prism 5 . Data are presented as mean values with standard deviation (SD) and categorical values as frequency counts and percentages. P < 0.05 was considered significant. All data analysis was performed using SPSS statistical software version 26.Statistical differences between groups were assessed by the nonparametric Mann–Whitney DDIT4 is a key molecule in the signal of autophagy, and the autophagy will prevent the cancer cell for death in the harsh microenvironment. This study used retrospective case-control study to explore the correlation analysis between gene mutation sites in the tissue of pancreatic cancer. We sequenced 15 pancreatic tissues to determine the DDIT4 gene mutation in the enrolled patients . The besDDIT4 correlated with tumor progression and affected the prognosis of patients with ovarian carcinoma . In ordePrevious literatures suggested that DDIT4 was closely related to autophagy in tumor cells . To furtBased on our experimental results and relevant literature, we summarized the relationship between DDIT4 3′-UTR mutation and pancreatic cancer. The DDIT4 gene mutation in pancreatic cancer cells leads to a base-point mutation in DDIT4 3′-UTR, and it may affect protein localization which may be involved in its biological function. The DDIT4/TXNIP complex located in the mitochondrion promotes the expression of ROS, which inhibited the dephosphorylation ability of ATG4B. And it promotes the increased amount of LC3 expression and the activation of autophagy. DDIT4 gene mutations may result in the antitumor resistance through abnormal protein localization in the pancreatic tumor cells .Our article found two novel gene mutations in the 3′-untranslated region of DDIT4 mRNA in PDAC. At the same time, we found a correlation between the expression level of DDIT4 and the type of gene mutation, and DDIT4 was colocated with LC3 obviously in pancreatic cancer. This paper showed that the two novel gene mutations in the 3′-untranslated region of DDIT4 mRNA may be a novel target in pancreatic cancer.We found two types of stable mutation in the DDIT4 mRNA 3′-UTR, and the most prevalent class of regulatory elements in the 3′-UTR is microRNA binding sites . A gene The expression levels of DDIT4 were regulated by a variety of factors, such as hypoxia , ionizinThe colocalization of DDIT4 and LC3 indicated that DDIT4 was highly expressed in pancreatic cancer tissues and its expression is involved in autophagy. DDIT4 signaling was connected to both autophagy which were involved in temozolomide drug resistance and the poor prognoses of glioblastoma multiforme patients . The ATFβ signaling were involved in pancreatic cancer resistance to gemcitabine/nabaxel [The high expression of DDIT4 not only promotes the increase of autophagy in pancreatic cancer tumor cells but also may be involved in tumor resistance by inhibiting the function of immune cells around the tumor . Meanwhi/nabaxel . A thera/nabaxel .The heterogeneity of cancer is ultimately related to drug resistance after long-term codevelopment of tumor and microenvironment, and the mutation of drug-resistant genes is the inevitable result which benefits the survival of tumor. The UTR mutation of DDIT4 is involved in autophagy of pancreatic cancer cells by regulating the expression of DDIT4, and it may be a potential biomarker for chemotherapy resistance and poor prognosis. The overexpression of ADAM28 in pancreatic cancer is closely related to the regulation of gemcitabine resistance, so it is a new prognostic biomarker in pancreatic cancer . High exThis article has some limitations. The survival time of patients with pancreatic cancer is very short, and it is difficult to use cohort study. Therefore, this study used retrospective case-control study to explore the correlation analysis between gene mutation sites and tumor self-dependence and to provide a new target for chemotherapy resistance and prognosis in the future. This article only captured the tumor tissue at a point in time and through the comprehensive analysis of the DDIT4 gene mutations in multiple tumor samples, but the evidence is indirect. In the future, if we are lucky enough to get the same tumor patients with multiple points in time of tissue or blood samples, we can directly observe the gene mutation during the progression of the tumor.In this study, we found a gene mutation in the 3′-UTR region of DDIT4, which may be associated with DDIT4 expression and tumor autophagy in pancreatic cancer tissues, and the further mechanistic research requires more work.


We aimed to determine whether children and adults with poorly controlled or more severe asthma have greater risk of hospitalisation and/or death from COVID-19.We used individual-level data from the Office for National Statistics Public Health Data Asset, based on the 2011 census in England, and the General Practice Extraction Service data for pandemic planning and research linked to death registration records and Hospital Episode Statistics admission data. Adults were followed from 1 January 2020 to 30 September 2021 for hospitalisation or death from COVID-19. For children, only hospitalisation was included.Our cohort comprised 35 202 533 adults and 2 996 503 children aged 12–17 years. After controlling for sociodemographic factors, pre-existing health conditions and vaccine status, the risk of death involving COVID-19 for adults with asthma prescribed low dose inhaled corticosteroids (ICS) was not significantly different from those without asthma. Adults with asthma prescribed medium and high dosage ICS had an elevated risk of COVID-19 death; HRs 1.18 (95% CI 1.14 to 1.23) and 1.36 (95% CI 1.28 to 1.44), respectively. A similar pattern was observed for COVID-19 hospitalisation; fully adjusted HRs 1.53 (95% CI 1.50 to 1.56) and 1.52 (95% CI 1.46 to 1.56) for adults with asthma prescribed medium and high-dosage ICS, respectively. Risk of hospitalisation was greater for children with asthma prescribed one (2.58 (95% CI 1.82 to 3.66)) or two or more (3.80 (95% CI 2.41 to 5.95)) courses of oral corticosteroids in the year prior to the pandemic.People with mild and/or well-controlled asthma are neither at significantly increased risk of hospitalisation with nor more likely to die from COVID-19 than adults without asthma. It is not clear if children or adults with asthma are at greater risk of hospitalisation and/or death from COVID-19 compared with the general population.Adults and children with poorly controlled or severe asthma are at significantly increased risk of hospitalisation from COVID-19 when compared with those without asthma, however, those with mild or well-controlled asthma are not.As the pandemic has progressed and more data has been gathered, it has become increasingly evident, at least as far as people with asthma are concerned, that the risks are not equal and perhaps the time has come to adopt more tailored strategies when developing guidelines and recommendations for vaccination policies aimed at protecting vulnerable populations from the risks of COVID-19.As part of the response to the COVID-19 pandemic, a number of studies have been undertaken to ascertain who is most at risk of developing severe disease, and who therefore should be prioritised for vaccination and subsequent boosters.The picture that has emerged from the evidence so far is not entirely clear. Although asthma is not currently in the top 10 comorbidities associated with death in people with COVID-19, it has been suggested that asthma may increase the risk of developing more serious disease and thus hospitalisation for COVID-19.The current evidence base has some notable limitations. To date, most studies have been conducted in populations hospitalised for COVID-19 rather than people who contract COVID-19 in the community, or during the first wave of the pandemic and thus likely to be subject to selection biases. In addition, most studies have been conducted in adults rather than in children and with relatively short follow-up times. Another important limitation is that most studies do not differentiate mild asthma from more severe asthma or between poorly and well-controlled asthma, while outcomes may differ between these groups.In this study, we investigated the effect of asthma on the risk of COVID-19 hospitalisation and death using a unique linked administrative dataset for an exceptionally large cohort of adults and children over the age of 12 years living in England. We compared COVID-19 outcomes  in people with and without asthma, and different severity of asthma. Our study aimed to answer the question as to whether children and adults with poorly controlled asthma have greater risk of hospitalisation and or death from COVID-19 and should be prioritised for vaccination or other interventions. In doing so, we aimed to bring some clarity to the seemingly conflicting/inconsistent evidence base to help policy-makers going forward.We used individual-level data from the Office for National Statistics (ONS) Public Health Data Asset, a unique cohort based on the 2011 census in England, and the General Practice Extraction Service (GPES) data for pandemic planning and research which are linked to death registration records and Hospital Episode Statistics (HES) hospital admission data. The ONS 2011 Census data were linked to the 2011–2013 NHS Patient Registers in order to obtain NHS numbers for each individual. Data were first linked deterministically using 24 different matching keys, based on a combination of forename, surname, date of birth, sex and geography (postcode or Unique Property Reference Number). Probabilistic matching was then used to attempt to match records that were not linked deterministically, using 13 different combinations of personal identifiers. Candidate matches were assigned to census records using the Felligi-Sunter probabilistic matching method. Of the 53 483 502 census records, 50 019 451 were linked deterministically. 555 291 additional matches were obtained using probabilistic matching .We restricted our sample to individuals who were aged 12 or over at the beginning of the pandemic. Of the 51 418 746 people enumerated at the 2011 Census in England and Wales, we excluded 2 832 087 people (5.5%) who could not be linked deterministically or probabilistically to the NHS Patient register, and 4 032 701 individuals (7.8%) who had died between the 2011 Census and 1 January 2020. An additional 6 350 661 people (12.4%) were not linked to the English primary care records, either because they did not live in England in 2019 , or because they were not registered with the NHS and were also excluded. After excluding 4261 individuals who had received their vaccine before the beginning of the vaccination campaign (8 December 2020), our sample consisted of 38 199 036 individuals  and 2 996 503 children aged 12–17, corresponding to 79.2% and 76.5% of the total respective populations in England (based on the 2020 mid-year population estimates).+ and 2 9Individuals in the study population were followed up from 1 January 2020 to 30 September 2021 for COVID-19 death, defined as a death where COVID-19 was recorded as an underlying or contributory cause of death on the death certificate as identified by two International Classification of Diseases and Related Health Problems (ICD-10 codes U07.1 (confirmed) or U07.2 (suspected). The secondary outcome was hospitalisation with COVID-19 between 1 January 2020 and 30 September 2021, defined as ICD-10 codes U07.1 (confirmed) or U07.2 (suspected). For children, we only included hospitalisations, as the number of deaths was too low to conduct a meaningful statistical analysis.Our control group was those without an asthma diagnosis the 2 years prior to the pandemic (1 January 2018 to 31 December 2019) and our exposure groups were: (1) asthma diagnosis and no ICS prescriptions in the year prior to the pandemic (1 January 2019 to 31 December 2019); (2) asthma diagnosis and low dosage ICS prescribed in the year prior to the pandemic (3) asthma diagnosis and medium dosage ICS prescribed in the year prior to the pandemic; and (4) asthma diagnosis and high-dosage ICS prescribed in the year prior to the pandemic. We also used oral corticosteroids (OCS) prescriptions as an exposure variable (as a measure of exacerbation frequency and thus poor control). For this, our control group was again no asthma diagnosis, and our exposure categories were: (1) asthma diagnosis and no OCS prescription in the year prior to the pandemic (1 January 2019 to 31 December 2019); (2) asthma diagnosis and one OCS prescription in the year prior to the pandemic and (3) asthma diagnosis and two or more OCS prescriptions in the year prior to the pandemic.Asthma diagnosis was defined by the presence of at least one relevant SNOMED code in the primary care record in the 2 years prior to the pandemic (1 January 2018 to 1 January 2020). The asthma definition has been validated for adults in a previous study using the Clinical Practice Research Datalink (CPRD) GOLD database against a reference standard of physician review of patient notes and has a high positive predictive value (>86%).We did not add any additional restrictions to determine whether the OCS prescription was for asthma or not, we simply required the individual to have received an asthma diagnosis in the previous 2 years and have received an OCS prescription under 300 mg for selected SNOMED codes. Given that acute exacerbations of asthma in adults and children over 12 are routinely treated with OCS (prednisolone) at a dosage level of 40–50 mg once a day for 5 days, OCS prescriptions were only counted if they were below 300 mg . This methodology has been used in previous studies.We adjusted for factors that could confound the relationship between asthma and COVID-19 hospitalisation or death. We adjusted for sex, age, region, ethnicity (10-categories), quintile of the Index of Multiple Deprivation (IMD) and several relevant pre-existing conditions, defined as per in the QCovid risk model .6 We alsAs a measure of differences in absolute risk of COVID-19 hospitalisation and death between people with asthma and the general population, we calculated age-standardised rates, whereby the age distribution within each group was standardised to the 2013 European Standardised Population. We calculated age standardised rates separately for men and women for adults (18 or over). For children (12–17), we calculated crude rates.To estimate the relative risk of COVID-19 mortality between people with a diagnosis of asthma and the general population, we fitted Cox proportional hazard models, adjusted for a range of potential confounding factors, using separate models for adults and children. We fitted several models, adjusting for confounding factors sequentially to assess how they affected the hazard ratios of having asthma. We used different model specifications for children and for adults. For adults, the first model was just adjusted for age and sex. Second, we further adjusted for socio-demographic factors, including region, ethnicity, and quintile of IMD. Region was adjusted for by estimating region-specific baseline hazard, to capture changes in infection rate over time in different areas. Third, we added comorbidities, hospitalisation in the previous year for any other reason than asthma, and OCS use except when OCS was the exposure variable. Finally, we added vaccination status as a time varying covariate. For children, the first two models were the same as for adults. However, in the third model we adjusted for hospitalisation in the previous year for any other reason than asthma.Our analytical sample consisted of 35 202 533 adults (aged ≥18 year) and 2 996 503 children aged 12–17 years who were alive on 1 January 2020 and living in England in private households. Over the period, there were 118 256 (0.3%) deaths involving COVID-19 and 331 063 (0.9%) COVID-19 hospitalisations in adults . In chilChildren with asthma had higher risk of COVID-19 hospitalisation over the period of study. The rate of COVID-19 hospitalisation in children with poorly controlled asthma (two or more courses of OCS) was 375.3 (206.9–543.8) per 100 000 children, compared with 94.4 (90.8–98.0) for children without asthma. COVID-19 hospitalisation rates were also elevated in children with a diagnosis of asthma who were not prescribed OCS, but to a lesser extent, with hospitalisation rates of 128.4 (112.6–144.1).Similarly, adults with asthma prescribed two or more courses of OCS in the year prior to the pandemic had a notably higher risk of death than those without asthma, with a HR of 1.60 (95% CI 1.55 to 1.67) . The relExamining adjusted HRs stratified by sex and age group, we found that the relative risks tended to be greater in the groups with lower absolute risk . The adjOur study is one of the most comprehensive, and certainly the largest, longitudinal cohort study to investigate COVID-19 hospitalisation and mortality in people with current asthma that has been conducted to date. We found that adults with mild and/or well-controlled asthma are neither at significantly increased risk of being hospitalised with COVID-19 nor more likely to die from COVID-19 than adults without asthma. However, those who recently required higher ICS dosage-based therapies  or who experience one or more exacerbations per year  as measured by OCS prescriptions, are potentially at increased risk of both hospitalisation and death. Specifically, we found that two or more courses of OCS in the preceding year was associated with an increase in hospitalisation in both children and adults and associated with death in adults.We also found that there was no difference in COVID-19 hospitalisation and death between adults with asthma prescribed low-dose ICS and those with no history of asthma, whereas there was a slightly increased risk in those with a diagnosis of asthma but not prescribed ICS, again suggesting that better control of asthma reduces relative risk of adverse COVID-19 outcomes. Finally, whereas our analysis indicates that the relative risks of COVID-19 hospitalisation and death are higher in women than men, and in younger as opposed to older age groups , it is important to note that the absolute risks were greater in men and in the over 50 s.Several researchers have alluded to the apparent inconsistencies in the literature regarding the vulnerability of people with asthma to COVID-19. In this context, it is noteworthy that many of the earlier studies that have suggested that people with asthma are at increased risk of severe COVID-19 were conducted in the first 6–9 months of the pandemic and predominantly in hospitalised patients.et al, while 14% of people admitted to hospital for COVID-19 (n=20 133) had asthma, a prior diagnosis of asthma was not a significant risk factor for COVID-19 mortality; however, prior diagnosis of other chronic diseases including chronic cardiac disease, chronic non-asthmatic pulmonary disease and chronic kidney disease were independently associated with in-hospital COVID-19 mortality.In contrast, later studies, including several conducted in community cohorts and therefore more representative of the asthma population, have failed to find strong evidence of an association between asthma and increased risk of poor outcomes, including hospitalisation, ICU admission and death from COVID-19.While, in common with other studies, we found that people with mild and/or well-controlled asthma were not necessarily at greater risk of COVID-19 hospitalisation and death than people without asthma we did see an increased risk among those with more severe asthma (prescribed ICS at medium or high doses as opposed to low) and whose asthma is less well controlled, determined by OCS prescriptions in the year prior. Our findings in this regard build on those from other studies, which have not had the advantage of being able to grade disease severity in terms of ICS dosage level but have instead used proxies—either number of inhaled treatments or recent OCS use or hospitalisation—to categorise people according to their disease severity.This study goes some way towards resolving some of the apparent inconsistencies in the literature surrounding asthma and COVID-19 which to a certain extent has been inevitable given the pace of the pandemic and urgent need for information on which to base decisions about vaccination priorities, among other interventions. Studies to date have been challenging to interpret into policy decisions due to a combination of factors, including limited cohort sizes, differing comparator arms used in studies, less granular disease management definitions, shorter follow-up, selected cohorts, not necessarily taking early shielding into account and most studies limited to hospitalised populations and the first wave of pandemic data when testing was more limited. All of these issues may generate biased results.The primary strength of our study is the use of a uniquely large, nationwide population-level dataset, created for pandemic planning and research purposes. This dataset is based on GPES  Data linked to the most recent census data, mortality records and HES. Our data cover around 80% of the population of England, and includes children aged 12 and over; however, we have not explored this question in children under the age of 12. By combining electronic healthcare records with self-reported data from the detailed 2011 census means we have been able to measure some key sociodemographic confounders with a high of accuracy. For instance, we used self-reported ethnicity from census data rather than ethnicity recorded in primary care or hospitalisation data, which is of lower quality and suffers from a high degree of missingness. The granularity of prescription information which has allowed us to tease out poor control from disease severity represents another major strength of our study. The main limitation is that the study population is limited to people enumerated at the 2011 census, and therefore did not include people who have since immigrated or were born between 2011 and 2020. As a result, it did not fully represent the population at risk. However, migrants tend to be young and the risk of COVID-19 mortality is low for young people. Finally, there are inevitably issues of misclassification with any study using routine electronic healthcare records. Where possible we have used validated definitions, and the team have many years of experience in using these data.In a rapidly evolving pandemic, keeping pace with the volume of new data and evidence is challenging. It also makes it difficult to provide straightforward answers to some of the key important policy questions, such as are people with asthma at a higher risk of poorer clinical outcomes from COVID-19? As the pandemic has progressed and more data has been gathered, it has become increasingly evident, at least as far as people with asthma are concerned, that the risks are not equal in that not all asthma is the same; those with mild/well-controlled asthma have a similar risk to the general population. It is only those with poorly controlled or severe disease that are at increased risk of serious COVID-19 adverse outcomes and may need prioritisation for vaccination and/or other treatment. Perhaps the time has come to adopt more tailored strategies when developing guidelines and recommendations for vaccination policies aimed at protecting vulnerable populations from the risks of COVID-19. It also important when planning public health policy and interventions not to focus on individual diseases, but to contextualise the strength of association between asthma risk and outcomes considering other chronic diseases. Whatever the risks to any one individual, the importance of disease control at all levels of disease severity is a consistent message and serves as a reminder that even in a time of COVID-19 the basics of routine healthcare should not be overlooked.Good disease management including treatment adherence leading to better disease control helps to limit the risk of poor outcomes. In a rapidly evolving pandemic, as information develops, messaging changes and when contextualising disease outcomes, it is important to consider relative and absolute risks.


Pragmatic language skills form the foundation for conversational competence, whereas deficits in this area are associated with behavioral problems and low literacy skills. Children who are deaf or hard of hearing demonstrate significant delays in this critical area of language. Our purpose with this research was to identify variables associated with pragmatic language ability in children who are deaf or hard of hearing.This was a longitudinal study of 124 children with bilateral hearing loss between 4 and 7 years of age living in Colorado. As part of a comprehensive speech and language assessment, pragmatic language skills were evaluated annually by using the Pragmatics Checklist.The children’s pragmatic skills increased significantly with age. Higher levels of pragmatic language ability at 7 years of age were predicted by (1) meeting Early Hearing Detection and Intervention 1–3–6 guidelines , (2) greater quantity of parent talk, (3) higher nonverbal intelligence, (4) lesser degrees of hearing loss, and (5) higher maternal education.With the findings of this study, we underscore the importance of pediatricians and other health care professionals counseling parents about the value of adherence to the Early Hearing Detection and Intervention 1–3–6 guidelines with regard to intervention outcomes. The strong association between amount of child-directed parent talk in the first 4 years of life and pragmatic language outcomes at 7 years of age emphasizes the need for professionals to encourage parents to talk to their children as much as possible. Pragmatic language competence is critical in face-to-face communication, and better pragmatic language skills also have been associated with success in educational settings.12 In contrast, deficits in pragmatic language ability have been associated with lower levels of literacy15 and an increased incidence of behavioral problems.17The pragmatic aspects of language can be defined as the rules governing the use of language in context.23 little is known about what child and family characteristics are associated with better pragmatic language outcomes, particularly in children who are deaf or hard of hearing. Researchers in previous studies have examined predictors of other aspects of language, such as vocabulary development, and have reported a variety of child factors to be related to better outcomes. These include lesser degrees of hearing loss28 and early enrollment in intervention.29 Parent variables, such as higher levels of maternal education, also have been associated with improved language outcomes for children who are deaf or hard of hearing.31 In studies involving children who are hearing, greater quantity of parent talk has been associated with better vocabulary outcomes.34 However, little is known regarding the impact of parent talk on pragmatic language development specifically, particularly in children who are deaf or hard of hearing.Although there has been an increase in research on pragmatic language development in school-aged children (with and without hearing loss) over the past decade,Considering the importance of pragmatic language ability, and the delays that persist for children who are deaf or hard of hearing, analyzing predictors and longitudinal development of this aspect of language may be used to identify factors that can be modified early in life to reduce or prevent delays in later childhood. Our purpose with this study was to identify factors associated with pragmatic language performance and growth in pragmatics skills over time. Specifically, the impact of the following child and parent characteristics was examined: (1) child’s chronological age; (2) child’s nonverbal intelligence quotient (IQ); (3) degree of hearing loss; (4) meeting the Early Hearing Detection and Intervention (EHDI) guidelines of screening, diagnosis, and early intervention by 1, 3, and 6 months of age, respectively; (5) mother’s level of education; and (6) quantity of child-directed parent talk.This was a longitudinal study of 124 children with bilateral, prelingual hearing loss from 3 years, 9 months to 7 years, 3 months of age . All participants lived in Colorado, had hearing parents, and were from homes in which the primary language was spoken English. Sign language was used consistently in conjunction with spoken language by 16% of the families. During the birth-to-3-year period, the families received early intervention services (1 hour per week) from the Colorado Home Intervention Program. One of the primary components of this program for all families involved teaching parents strategies to maximize their child’s communication skills. See 35 Only 4% of the children scored >2 SD below the test mean of 100.The majority (90%) of the children had no additional disabilities thought to interfere with speech or language development. The remaining 10% reported additional disabilities ranging from sensorimotor integration issues to cognitive delay. The children’s nonverbal IQs ranged from 58 to 140  on the basis of the Leiter International Performance Scale-Revised.The children’s degree of hearing loss ranged from mild to profound, and all used either hearing aids and/or cochlear implants . See further details in 5 a parent-report instrument designed to examine children’s use of 45 different pragmatic language skills . For each item, parents indicated if their child demonstrated the skill and, if so, whether they did so nonverbally, using 1- to 3-word phrases, or using sentences of ≥4 words. Children’s scores were calculated on the basis of the proportion of items they demonstrated when using sentences of 4 words or more. To ease interpretation, this proportion was rescaled to a range of 0 to 10, indicating the corresponding decile  of items the child demonstrated using sentences containing ≥4 words. For example, a score of 6.8 indicates that a child demonstrated 68% of the items when using sentences of ≥4 words.The children’s pragmatic language skills were measured by using the Pragmatics Checklist,35 and the full-scale IQ score was entered as a continuous variable.The chronological age of the child in months at the time of each assessment was used to assess growth in pragmatic language skills over time. Nonverbal cognitive ability was assessed by using the Leiter International Performance Scale-Revised,All families completed a demographic form. Children were categorized as meeting the EHDI 1–3–6 guidelines or not  on the basis of the parents’ report of whether the child received a hearing screen at birth, the age the child’s hearing loss was confirmed, and the age they started early intervention. Maternal level of education was also obtained from the demographic form and entered as a continuous variable (years of education completed).Audiologic records were used to determine degree of hearing loss. Children were categorized into 2 groups based on their better-ear pure tone average: mild to moderate hearing loss (coded as 0) versus moderate-severe through profound hearing loss (coded as 1).36 The number of words produced by the parent was averaged across the samples for each participant. To account for the fact that a small number of samples were slightly shorter than 25 minutes, parent talk was quantified in terms of parent words per minute.Quantity of parent talk directed to the child during the toddler and preschool years was based on 25-minute parent-child free-play language samples collected during a previous study when the current participants were 12 to 51 months of age (mean age = 32.2 months). All language samples were obtained in an environment that was familiar to the child and parent. Specifically, samples obtained during the 12- to 39-month period were collected in the child’s home, and those gathered when the child was 40 to 51 months of age were taped in a quiet room at the child’s school or local library. All language samples were gathered before collection of the pragmatics scores that were examined in the predictive model of this study. One to 6 language samples were collected from each child (mean = 2.25). See The proportion of children in each category of the dichotomous predictor variables are presented in For the primary analyses, investigators used a 2-level hierarchical linear model with a random intercept to evaluate intraand inter-individual differences in pragmatics scores. Age was centered on 84 months, whereas all other predictors were centered on their corresponding mean. This procedure resulted in the overall intercept being the adjusted mean predicted pragmatics score at 84 months of age.Each child’s observed growth was modeled at level 1, with the child’s age in months at the time of an assessment as the level 1 predictor. Nonvarying child and parent characteristics  were then used as level 2 predictors of both a child’s intercept  and growth . Preliminary screening and regression diagnostics revealed that the skew and kurtosis of the residuals were small and nonsignificant, with the absolute magnitude of all residuals <3. An examination of residual plots versus all predictors found no heteroscedasticity. The maximum variance inflation factor across all predictors was <1.11, suggesting minimal multicollinearity.r = 0.22.In An initial “null” model simply examined variation in pragmatics scores across children and time with no predictors included. Adding the level 1 predictor of child age at the time of each assessment accounted for 52.6% of the level 1 variance in pragmatics scores . The 5 level 2 variables were then added as predictors of the intercept term: in essence, assessing whether these child and parent characteristics had an overall impact on pragmatics performance. These 5 level 2 variables  accounted for 42.4% of the level 2 mean child-to-child variance in pragmatics scores. Subsequent analyses were also used to examine whether the level-2 variables predicted growth in pragmatics skills . None were statistically significant, and so these were not included in the final model. The final model is presented in b = 0.15, P < .001). Focusing on the child-level characteristics, degree of hearing loss was related to pragmatics scores, with children diagnosed with moderate or severe to profound hearing loss performing the equivalent of 0.28 SD lower than those with mild or moderate hearing loss . Leiter full-scale IQ scores also were related to pragmatics scores, with an increase of 0.08 in a child’s score for each 1-point increase in Leiter IQ . In essence, a 15-point increase in Leiter IQ scores  was associated with a 0.30 SD increase in pragmatics performance.As reflected in b = 0.04, P = .003). In this case, a 1 SD increase in the number of words spoken by the parent was associated with the equivalent of a 0.19 SD increase in predicted pragmatics performance. Finally, meeting the EHDI 1–3–6 guidelines was also a significant predictor of pragmatics scores . Specifically, children who met the EHDI 1–3–6 guidelines had pragmatics scores that were 0.26 SD higher than those who did not meet these guidelines.“Parent words per minute” was also a significant predictor of pragmatics scores  meeting EHDI 1–3–6 guidelines, (2) greater quantity of parent talk, (3) higher nonverbal IQ, (4) lesser degrees of hearing loss, and (5) higher maternal level of education. The relationships among these variables and between the predictor and outcome variables are likely complex, making the relative causal impacts difficult to ascertain without further research involving larger samples. In addition, although these 5 variables accounted for 42% of the variance in pragmatic skills, there are certainly additional uncontrolled factors  that also contributed to pragmatic language outcomes.24 nonverbal IQ,38 lesser degrees of hearing loss,28 and higher maternal education.31 With this study, we extend these findings to the pragmatic area of language.The findings of the current study are consistent with those of previous studies of children who are deaf or hard of hearing in which researchers found an association between other aspects of language  and meeting EHDI 1–3–6 guidelines,In the current study, we indicate that timely identification of hearing loss and early intervention are critical for the optimal development of pragmatic skills. For context, the observed effect size for meeting EHDI 1–3–6 guidelines was on par with 4.32 years of additional maternal education or essentially equivalent to the difference between mild or moderate hearing loss and moderate-severe to profound hearing loss. In this study, all participants had been enrolled in Colorado Home Intervention Program, an early intervention program in which the providers have graduate-level training and expertise specific to both deafness and early childhood development. It is likely that the benefits of receiving intervention early are maximized when these services are provided by highly qualified professionals, and the positive impact of meeting EHDI guidelines may be less pronounced when early intervention is provided by less skilled personnel.39 Given previous findings that maternal education and other indicators of socioeconomic status are related to amount of parent input,39 it is likely that, within the current study, a complex relationship exists between amount of parent talk, maternal level of education, and child language outcomes.The amount of parent talk (quantified as the number of parent words directed to the child during free-play interactions) when the participants were younger (ages 1–4 years) also was a significant predictor of the children’s pragmatic language ability when they were 7 years of age. This finding is consistent with studies of children who are hearing in which greater quantities of parent talk have been associated with better child vocabulary and other language outcomes.40 found that higher quantity of parent talk during parent-child interactions was associated with the parents’ use of more diverse vocabulary, longer utterances, and the use of a variety of child languageenhancing strategies including expansions and imitations of the child’s utterances. Hart and Risley33 also posit that quantity of speaking is linked to the amount of quality features in the language used. Authors of these studies, in combination with the current investigation, suggest that early intervention focused on increasing both the quantity and quality of parents’ communication with their child who is deaf or hard of hearing may result in improved child language outcomes.The significant associations found in previous studies between the quantity of parent talk and child language skills has prompted researchers to examine if amount of parent talk serves as a proxy for the quality of parental input. Coady et alIn this study, a variety of variables were found to predict pragmatic language abilities of children who are deaf or hard of hearing at 7 years of age. Of these, 2 factors  can be positively influenced by pediatricians and other health care professionals, such as audiologists, speech-language pathologists, and otolaryngologists. Specifically, pediatricians, otolaryngologists, and audiologists can support the goals of EHDI by urging families whose child has referred on a newborn hearing screen to seek diagnostic hearing evaluation and enrollment into early intervention as soon as possible. One of the primary benefits of early intervention is its role in providing parents with strategies that will enhance both the quantity and quality of their communication with their child, which is another factor found in this study to predict better pragmatic language skills. This strong association between amount of child-directed parent talk in the first 4 years of life and pragmatic language outcomes at 7 years of age emphasizes the need for a team approach with both early interventionists and pediatricians encouraging parents to talk to their children as much as possible.


Cross-sectional screening programs are used to detect and refer individuals with non-communicable diseases to healthcare services. We evaluated the positive predictive value of cross-sectional measurements for Diabetes Mellitus (DM) and hypertension (HTN) as part of a community-based disease screening study, ‘Vukuzazi’ in rural South Africa.We conducted community-based screening for HTN and DM using the World Health Organization STEPS protocol and glycated haemoglobin A1c (HbA1c) testing, respectively. Nurses conducted follow-up home visits for confirmatory diagnostic testing among individuals with a screening BP above 140/90 mmHg and/or HbA1c above 6.5% at the initial screen, and without a prior diagnosis. We assessed the positive predictive value of the initial screening, compared to the follow up measure. We also sought to identify a screening threshold for HTN and DM with greater than 90% positive predictive value.Of 18,027 participants enrolled, 10.2%  had a screening BP over 140/90 mmHg. Of those without a prior diagnosis, 871 (47.6%) received follow-up measurements. Only 51.2% (451) of those with completed follow-up measurements had a repeat BP>140/90 mmHg at the home visit and were referred to care. To achieve a 90% correct referral rate, a systolic BP threshold of 192 was needed at first screening. For DM screening, 1,615 (9.0%) individuals had an HbA1c > 6.5%, and of those without a prior diagnosis, 1,151 (71.2%) received a follow-up blood glucose. Of these, only 34.1% (395) met criteria for referral for DM. To ensure a 90% positive predictive value i.e. a screening HbA1c of >16.6% was needed.A second home-based screening visit to confirm a diagnosis of DM and HTN reduced health system referrals by 48% and 66%, respectively. Two-day screening programmes for DM and HTN screening might save individual and healthcare resources and should be evaluated carefully in future cost effectiveness evaluations. Type 2 diabetes mellitus (DM) and hypertension (HTN) are increasing in prevalence worldwide and are major contributors to the rise in the global burden of non-communicable diseases (NCDs) . It is eIn response to the growing burden of undiagnosed DM and HTN in South Africa, there are increased efforts to enhance disease detection through screening. This includes routine clinic-based screening for NCDs , but als89101112132. The area is one of the lowest ranked in terms of health and socioeconomic status and is catered to by 11 government-run public health clinics [From May 2018 to Dec 2019, the Africa Health Research Institute (AHRI) conducted a community-based survey, named ‘Vukuzazi’ that screened individuals for infectious (HIV and TB) and non-communicable diseases (hypertension and diabetes)  in its D clinics 17. A cenAll residents aged 15 years and above in the DHS were eligible for participation. Study staff visited all households in the surveillance area and invited eligible household members to attend a mobile health screening fair, which traversed the surveillance area over the course of an 18-month period to conduct study procedures.Study staff administered standardized questionnaires to collect current and past medical history, including participation in care and medication use for DM and HTN during the health screening fair. Blood pressure was recorded using Omron portable electronic sphygmomanometer  using the World Health Organization STEPs protocol , three mWe calculated BP using the average of the last two of three measurements collected. Elevated BP was defined as a systolic BP ≥140 mm Hg and/or diastolic BP ≥90 mm Hg, based on South African Department of Health Primary Care Guidelines . For parIndividuals with an HbA1c > 6.5% at the health fair and not currently on diabetes treatment were also seen at their homes by a study nurse for a point-of-care blood glucose measurement. Blood glucose testing using a portable capillary sample was used in place of HbA1c for the home-based confirmation measurement because it is the standard of care for diabetes diagnosis in South Africa . ParticiFor this analysis, we included individuals attending the Vukuzazi health fair who 1) screened positive for elevated BP or elevated HbA1c at the health fair and did not report being on therapy for HTN or DM, respectively; and 2) were visited at home by a study nurse for confirmatory disease measurement. Study analytic samples were divided it into sub-samples of those with elevated BP and those with elevated HbA1c at the health fair. We graphically depicted and correlated initial and confirmatory systolic and diastolic BP measurements and glucose tolerance measurements between the health fair and confirmatory visits. We then estimated the positive predictive value of the initial screen for elevated BP (elevated diastolic or systolic) and HbA1c measures by comparing them to a reference standard defined as sequentially positive screens at both the health fair and at the home visit). We then fitted a logistic regression model with a positive sequential screen at both the health fair and the home visit as the outcome of interest, this allowed us to predict marginal probabilities and to estimate how changes in BP and HbA1c at the screening visit increased the probability of a confirmed diagnosis after two visits. Finally, we determined the threshold of initial screening BP and HbA1c that would result in >90% of those being referred as having a confirmed disease after a second measure. In a sensitivity analysis, we excluded individuals from the DM sample with a confirmatory non-fasting blood glucose between 7.0–11.0 mmol/L, who might have a diagnosis of diabetes that cannot be determined by their non-fasting status. All data analysis was conducted using R version 4.0.2 .The Vukuzazi Study protocol was reviewed and approved by the Biomedical Research Ethics Committee at the University of KwaZulu-Natal (BE560/17), by the Ethics Committee of the London School of Hygiene (#14722) and by the Partners Institutional Review Board (2018P001802). All study participants gave written informed consent.Of the 18,007 participants who had their BP measured at the Vukuzazi health fair, 1,831 (10.2%) had high BP defined as either a systolic BP at least 140 mmHg or diastolic BP over 90mmHg  of DM and HTN, single-measure community-based programs might serve as an efficient prompt for initiating care engagement. However, in settings such as rural South Africa, where the public health system suffers from significant congestion and limited human resources for health, cross-sectional NCD screening programs run the risk of overburdening health services and transferring costs of over-diagnosis from the screening programs to the patient and public healthcare system.The large and growing burden of HTN and DM in South Africa, along with the increasing appreciation that the majority of people with these conditions are unaware of their condition, requires urgent attention . Among t89101112131214Creative solutions that promote screening and increasing awareness of NCDs, but also prevent over-burdening of healthcare systems are needed. In our program, we provided a follow-up home visit prior to referring into the health system. Although this is likely to increase the accuracy of referral, we have yet to learn whether it resulted in improved retention in care. The additional costs and time required for second visits to either the patient or the healthcare system must also be considered. Other programs, such as the ComHIP program in Ghana, are currently evaluating community-based approaches to HTN care, that extends out of clinic services to include follow-up measurements and provision of medicines . Effecti26We also sought to investigate whether more restrictive thresholds for referring to HTN and DM after an initial screen would be beneficial. However, we found that extremely high thresholds for systolic BP (192mm Hg), diastolic BP (123 mm Hg) and HbA1c (16.6%) were required to ensure that 90% of those referred would have confirmatory repeat measure on a second day. At these thresholds, we would have missed approximately 92% of HTN and 97% of DM cases who met criteria for treatment after sequential screening. Thus, our results do not suggest that there is a single higher screening threshold that would improve the positive predictive value of community-based screening without excluding a large proportion of people who do potentially require care. Prior studies have also shown that concomitant HTN screening along with HIV testing may lead to overdiagnosis of elevated BP due to transient elevations around the time of the HIV testing . ConsequOur study should be interpreted in the context of a number of limitations. This screening program was conducted recently, so we do not yet have data on the resulting linkage to and retention care which resulted from the addition of a nurse home visit to confirm diagnosis and initiate the referral. Due to the nature of the study, we were not able to assess the number of participants who may have been false negatives at the health fair as they were not followed up. Furthermore, using the second visit measure as confirmatory raises the possibility missing legitimate cases with elevated measures who had normal readings at the follow-up leading under detection of disease. Lacking a gold standard of diagnosis, the current study cannot directly assess the accuracy of a single measure versus two consecutive measures. Our study was not set up to collect health system resources and costs, but future studies should carefully evaluate the tradeoffs between mass NCD screening and referrals, with the additional costs associated with repeated measures prior to referral. The use of 90% PPV to estimate an optimal threshold was not justified by prior literature and a less stringent value could have been used, however we feel this does not affect the overall message that a single measurement should not be used to refer individuals to health care settings. Finally, our study used HbA1c as an initial screen, with a fasting blood glucose as a confirmation of DM to account for South African guidelines and practice, but only a proportion of the confirmatory tests were done in the fasting state. Nonetheless, our false positivity rate for an initial screen remained high when we excluded individuals with non-fasting measures in the range between 7 mmol/L and 11 mmol/L.Single measurement screening for HTN and DM in South Africa resulted in approximately a 50% rate of potentially unnecessary or premature referrals into the health sector for these conditions. Careful consideration of the potential benefits and risks of such screening programs will be essential to ensure they achieve their intended goal of improving NCD awareness and control. Cost-effectiveness and tradeoffs of such strategies versus repeated measure testing and/or community-based delivery of NCD care should be evaluated to further optimize care in such settings.The additional files for this article can be found as follows:10.5334/gh.1083.s1Supplementary Table 1.Demographic characteristics of complete home visits compared to LTFU.10.5334/gh.1083.s2Supplementary Table 2.Vukuzazi Study Team.