IntroductionEpilepsy is a burdensome disorder for affected individuals and community. There is limited data available on the epidemiological aspects of seizures in Pakistan and further research is necessary. We aimed to fill this gap by studying this information in epilepsy patients presenting to our neurology department. The purpose of this study is to evaluate the causes and types of seizures among the target population.MethodThis is a cross-sectional study conducted at the Department of Neurology, Dr. Ruth K.M. Pfau Civil Hospital Karachi. In this study we evaluated the causes and types of seizures among patients presenting to our department during the two-year study duration (January 2018-December 2019). Informed consent was taken. Detailed history was taken including features of seizure episodes, age at first seizure, family history and comorbid conditions. Relevant investigations were carried out. The data was compiled to deduce the relevant information using SPSS v20.0. T-test and Chi-square were used for analyzing the data.ResultsA total of 996 patients presented during the study duration. Primary seizures were found in 58% cases while secondary seizures were found in 42% cases. This distribution was more equal in children with 49.6% primary seizures and 50.4% secondary seizures; the gap widened in adults with 64.3% primary seizures and 35.7% secondary seizures. The most common cause of secondary seizures was neonatal encephalopathy which was present in 18.7% patients, followed by traumatic head injury in 18.2% patients. Central nervous system (CNS) infection was the cause in 17.9% patients, cerebral tumors in 14.1% patients, stroke in 11.5%, metabolic encephalopathy in 7.4%, febrile seizures in 6.5% and CNS malformations in 5.7% patients. The top three causes in children were neonatal encephalopathy (28.3%), CNS infections (19.3%) and febrile seizures (12.7%). Adults with secondary seizures were diagnosed most often with head trauma (25.2%), cerebral tumors (19.9%) and stroke (18.4%) as causative factors. The most common type of seizures was generalized onset tonic-clonic seizures which was found in 73.0% patients followed by focal to bilateral tonic-clonic seizures in 8.9% patients. Other types of seizures included focal aware seizures in 5.0%, mixed seizure types in 4.2%, focal impaired awareness seizures in 3.1%, absence seizures in 2.7%, myoclonic seizures in 2.0% and atonic seizures in 1.0% patients. Seizures in children were mostly generalized onset tonic-clonic seizures (75.4%), mixed seizure types (5.7%) and focal to bilateral tonic-clonic seizures (5.2%). In adults the three most common types corresponded to the overall result: generalized onset tonic-clonic seizures (71.2%), focal to bilateral tonic-clonic seizures (11.6%) and focal aware seizures (6.6%).ConclusionWe found that the most common cause of seizures overall in our study population was primary seizures, though primary and secondary seizures were more evenly present in children. Among secondary causes neonatal encephalopathy stood out as the most common cause in children; head trauma was the predominant cause in adults. Most common type of seizures overall and in adults was generalized onset tonic-clonic seizures, followed by focal to bilateral tonic-clonic and focal aware seizure types. Pediatric patients presented most often with generalized onset tonic-clonic seizures, followed by mixed seizure types and focal to bilateral tonic-clonic seizures. Approximately 10% of the world’s population experience seizures at least once in life . PakistaThe causes of seizures are diverse. They can be primary, or secondary with vascular, infective, metabolic, neoplastic, degenerative and genetic causes. Head injuries can also cause seizures either immediately or many years later. In the elderly, stroke and neurodegenerative conditions frequently lead to seizures .The aim of this study is to evaluate the causes and types of seizures among patients presenting to a tertiary care hospital in Karachi. Current data in this regard will help the policy makers in ensuring availability of the best drugs based on seizure types and causes. By identifying the most common causes of epilepsy, this study also intends to create opportunity and awareness for preventing these causes.This is a cross-sectional study conducted at the Department of Neurology, Dr. Ruth K.M. Pfau Civil Hospital Karachi. In this study we evaluated the causes of seizures among patients presenting to our department during the two-year study duration (January 2018 to December 2019). The study was approved by the institutional review board. Trained doctors were asked to interview the patients after taking informed consent. Demographic variables such as age, gender and socio-economic status were recorded. Detailed history was taken including features of seizure episodes, age at first seizure, family history and co-morbid conditions. Complete physical examination was performed. Baseline investigations were ordered such as complete blood picture, liver function tests, renal function tests, serum electrolytes, serum urea and creatinine levels. Causes of seizures were evaluated using detailed history and diagnostic modalities such as electroencephalogram (EEG), magnetic resonance imaging (MRI) brain, computed tomography (CT) brain scan, and cerebrospinal fluid (CSF) sampling. MRI was performed in majority of patients while CT scan was done in only a few patients in whom MRI was not necessary for diagnosis. CSF studies were reserved for those patients in whom infective or inflammatory causes were suspected. Seizures were diagnosed and classified based on the criteria defined by International League Against Epilepsy commission on classification and terminology of seizures . PatientA total of 996 patients presented during the study duration. This makes 10.5% of the total number of 9444 patients who presented to neurology department in this period. The mean age of our patients was 21.4 ± 3.2 years. Among them 534 (53.6%) were males and 462 (46.4%) were females  of total cases while secondary seizures were found in 418 42%) cases. Among pediatric patients primary and secondary seizures were more evenly distributed - primary seizures 207 (49.6%) and secondary seizures 212 (50.4%). Adult patients with primary seizures were 371 (64.3%) and 206 (35.7%) adults presented with secondary seizures  patients, followed by traumatic head injury in 18.2% (n = 76) patients. CNS infection was the cause in 17.9% n = 75) patients, cerebral tumors in 14.1% (n = 59) patients, stroke in 11.5% (n = 48), metabolic encephalopathy in 7.4% (n = 31), febrile seizures in 6.5% (n = 27) and cerebral malformations in 5.6% (n = 24) patients. The foremost cause of secondary seizures in pediatric population was neonatal encephalopathy which was found in 28.3% (n = 60), followed by CNS infections in 19.3% (n = 41). Febrile seizure was the cause in 12.7% (n = 27), head trauma in 11.3% (n = 24), cerebral tumors in 8.5% (n = 18), cerebral malformations in 8.5% (n = 18), metabolic encephalopathy in 6.6% (n = 14) and stroke in 4.7% (n = 10). Most prominent among the causes of secondary seizures in adults was head trauma which was found in 25.2% (n = 52), followed by cerebral tumors in 19.9% (n = 41) patients. Other causes were stroke in 18.4% (n = 38), CNS infections in 16.5% (n = 34), neonatal encephalopathy in 8.7% (n = 18), metabolic encephalopathy in 8.2% (n = 17) and cerebral malformations in 2.9% (n = 6) patients  patients, followed by focal to bilateral tonic-clonic seizures in 8.9% (n = 89) patients. Other types of seizures found in our study population included focal aware seizures in 5% (n = 50), mixed seizure types in 4.2% (n = 42), focal impaired awareness seizures in 3% (n = 31), absence seizures in 2.7% (n = 27), myoclonic seizures in 2% (n = 20) and atonic seizures in 1% (n = 10) patients. Among the pediatric population most common type of seizures was generalized onset tonic-clonic seizures in 75.4% (n = 316), followed by mixed seizure types in 5.7% (n = 24). Other seizure types in pediatric patients were focal to bilateral tonic-clonic in 5.2% (n = 22), absence seizures in 4.8% (n = 20), focal aware seizures in 2.9% (n = 12), myoclonic seizures in 2.9% (n = 12), atonic seizures in 1.9% (n = 8) and focal aware seizures in 1.2% (n = 5). Among the adult patients most common type of seizures was generalized onset tonic-clonic seizures in 71.2% (n = 411), followed by focal to bilateral tonic-clonic seizures 11.6% (n = 67). Other seizure types in adults were focal aware seizures in 6.6% (n = 38), focal impaired awareness seizures in 4.5% (n = 26), mixed seizure types in 3.1% (n = 18), myoclonic seizures in 1.4% (n = 8), absence seizures in 1.2% (n = 7) and atonic seizures in 0.3% (n = 2)  patients while abnormal EEG was found in 438 (44%) patients. Among abnormal EEGs interictal epileptiform abnormalities alone were found in 73.0% (n = 320), encephalopathy alone in 17.8% (n = 78) and both interictal epileptiform abnormalities and encephalopathy in 9.2% (n = 40) patients . The cause of seizures could only be evaluated in 38.4% of their study population. Adequate management of epilepsy was only received by 27% of urban patients and 2% of rural patients .According to previous studies the main cause of seizures in elderly is stroke which accounts for 30-70% of cases. Cerebral tumors cause 10-15% of seizures in this population while metabolic disturbances are responsible for less than 10% seizures. Other causes include head injury, CNS infections and neurodegenerative disorders . In our Kaur et al. conducted a study on the causes of seizures among adults admitted to a tertiary care setup in India. The most common cause of seizures in their study population was stroke followed by idiopathic causes and CNS infections. Cerebral tumors accounted for 10% of cases while metabolic disturbances were responsible in 12% patients. The most common cause of generalized onset tonic-clonic seizures was idiopathic while the most common cause of focal seizures was stroke. Status epilepticus was most often caused by metabolic derangements. They concluded that advanced age led to reductions in incidence of generalized seizures and focal seizures became more predominant as age progressed . Mac et In our study, the mean age was 21.4 ± 3.2 years. In studies conducted in Pakistan and other underdeveloped countries in Asia, the mean age for epileptic patients lies between 15-20 years. However in developed countries epilepsy has a bimodal distribution. The first peak is after few years of birth whereas the other peak occurs after 65 years of age . Most ofUllah et al. in 2018 conducted an epidemiologic study on the characteristics of epileptic patients in Khyber Pakhtunkhwa (KPK) province of Pakistan. The mean age of their study population was 18 ± 8 years with majority of patients being male. Most patients from this study belonged to low socio-economic status. The characteristics associated with poor response to management included low socio-economic status, non-compliance to therapy and generalized onset tonic-clonic seizures .Our study found that patients with epilepsy represented 10.5% of the total patient turnover in neurology department of our hospital. Considering the vast number of neurological illnesses this number looks a bit high. This can probably be explained by the fact that internal medicine departments and general practitioners often feel confident in treating some commonly presenting neurological diseases like headache and stroke, but most of the epilepsy patients are referred to neurology services. We also looked into the EEG patterns of our patients and found that 56% of them had normal EEG. 32.2% patients had interictal epileptiform abnormalities, 7.8% had encephalopathy pattern and 4% had both interictal epileptiform abnormalities and encephalopathy pattern. McGinty et al. found that 54.4% of their patients had normal EEG, 24.6% had non-specific abnormalities and 21.1% patients demonstrated interictal epileptiform abnormalities .The limitation of this study is that it represents the patients presenting to a single hospital and therefore generalization over the whole population may not be appropriate. Major strength of this study was a significant sample size spread over two years that minimize the chances of false representation of the actual state of affairs.Neonatal encephalopathy and head trauma were responsible for secondary epilepsy in majority of pediatric and adult population respectively in our study. Maternal and neonatal health has always been a major concern in Pakistan. This study, by finding neonatal encephalopathy as the leading cause of secondary epilepsy in children, reinforces the need for improving this crucial aspect of society health. Bike riders are frequently seen without helmets on all the major roads of Karachi. Head trauma was consequential for the most number of adult patients in this study; this underpins the need for creating awareness and perhaps implementing more stringent measures to eliminate this harmful habit among the population. Further studies on the causes and types of epilepsy in Pakistan are required as these factors differ between populations and hence the management strategies also differ consequently.This study provides an insight into an under-researched area of epilepsy in Pakistan. The causes and types of seizures dictate the best possible treatment options. We found that the most common cause of seizures in our overall study population was primary seizures, though primary and secondary seizures were more evenly present in children. Among secondary causes neonatal encephalopathy stood out as the most common cause in children; head trauma was the predominant cause in adults. Most common type of seizures overall and in adults was generalized onset tonic-clonic seizures, followed by focal to bilateral tonic-clonic and focal aware seizure types. Pediatric patients presented most often with generalized onset tonic-clonic seizures. Mixed seizure types and focal to bilateral tonic-clonic seizures were the next most common type of seizures in children. Further studies are needed in Pakistan so that conclusive data is accumulated in this regard to aid in making better decisions to combat this common disease.


L. bulgaricus, S. thermophilus, B. lactis and L. acidophilus were similar in all yoghurt samples at day 1. The maximum viability loss of probiotics was observed in CTL (p < 0.05). The lowest viability loss of probiotics was observed in AE5 samples (p < 0.05). The acidity, water holding capacity and viscosity were increased with the addition of APPE. No significant effects were observed on milk fat and total solid contents of probiotic yoghurt with the addition of APPE. The total phenolic contents of probiotic yoghurt increased significantly as 0.59, 0.71, 0.97, 1.18, 1.35 in AE1, AE2, AE3, AE4 and AE5, samples respectively. It was observed that AE3 and AE4 samples had better taste, flavour and colour with good texture. The survival of probiotics and antioxidant activity of the yoghurts were enhanced with the addition of APPE. In conclusion, apple peels could be successfully used as prebiotic in yoghurt with increased viable counts of probiotics.The aim of the current study was to evaluate the effect of apple peel polyphenol extract (APPE) on the physicochemical and microbiological properties of probiotic yoghurt. Five concentrations of APPE were added in probiotic yoghurt as: (1) CTL, control without APPE; (2) AE1, addition of 1% APPE; (3) AE2, addition of 2% APPE; (4) AE3, addition of 3% APPE; (5) AE4, addition of 4% APPE; and (6) AE5, addition of 5% APPE. The prepared probiotic yoghurt was stored at 4 °C for 21 days and analyzed for physicochemical and microbiological properties. The initial viable count of  Lactobacilli and Bifidobacteria are expressed in over ninety percent of probiotic items and popular among health-conscious societies [Functional yoghurt products involve the inclusion of probiotics, prebiotics or a mixture of both . Probiotocieties . The several bioactive elements from natural sources have nutritional benefits, sensual attributes, physiochemical properties and therapeutic values . PolypheIn Pakistan, the total production of apple during 2018–2019 was about 565,000 tones . Apple pLactobacillus delbrueckii subsp. bulgaricus and Streptococcus salivarius subsp. thermophilus) and probiotics strains (Bifidobacterium lactis BB-12 and Lactobacillus acidophilus La-5) was obtained from Sacco . All these cultures were kept in a freezer at −20 °C.This experiment was conducted in the microbiological and physicochemical laboratory, Department of Dairy Technology, University of Veterinary and Animal Sciences . Buffalo milk was obtained from the UVAS Dairy Farm. The yoghurt starter culture  were evaluated on the basis of total flavonoid content (TFC), total phenolic contents (TPC) and antioxidant activity.A solid phase extraction (SPE) column was used to pre-treat prior to the total extractable polyphenolic contents analysis to remove the possible interference of sucrose and vitamin C with the Folin-Ciocalteu reagent. The total phenolic content (0.05 mL) of apple peels was measured by the colorimetric method of Folin-Ciocalteu . AbsorbaL. bulgaricus and S. thermophilus) and probiotic strains (L. acidophilus and Bifidobacterium lactis) according to company (Sacco) description, each in cleaned sterilized plastic cups at 42 °C in incubator until the required acidity (pH 4.6). All yoghurt samples were stored at 4 °C and evaluated after 1, 7, 14, and 21 days. Every treatment was performed in triplicate.Probiotic yoghurt was prepared with different treatments of apple peel polyphenol extract (APPE) along with a control. The buffalo milk was standardized at 11% solids non-fat and 4% fat content. Milk was homogenized and pasteurized at 85 °C for half hour . The milL. acidophilus and B. lactis strains were incubated on selective de man rogosa and sharpe (MRS) agar with sorbitol and MRS-NNLP  agar, respectively. The viability of S. thermophilus was determined by a selective media of M17 agar. The media plates kept in aerobic conditions at 37 °C for two days. The selective media reinforced clostridia agar (RCA) used for L. bulgaricus under anaerobic conditions for two days at 42 °C [The viable count of yoghurt starter culture and probiotic microbes was performed after 1, 7, 14 and 21 days. The sample and dilution preparation for viable count and microbiological inspection was performed according to IDF standard . The couat 42 °C .Total solids (TS), milk fat, acidity and pH were measured according to the methods proposed by Association of Official Analytical Chemists . TS contg for 10 min at 20 °C. The expelled whey (EW) drained and sample weighed as grams. The WHC was calculated as:The viscosity of the yoghurt was calculated, after mixing the sample for 60 s, with the help of a model DV2T viscometer  at 4 °C. Samples were analysed using spindle number 4 at 12 rpm and data were recorded in centipoise (Cp) as duplicate . The watg for 120 s, followed by incubation for 30 min. Absorbance recorded at 517 nm in visible section of spectrum. The antioxidant activity was measured by calculating the free radical scavenging ability of probiotic yoghurt with DPPH inhibition.Total phenolic contents (TPC) (0.05 mL) was measured according to the Folin Ciocalteau colorimetric procedure as adopted by Moo-Huchin et al. . AbsorbaSensory quality evaluation for the probiotic yoghurt was done using a descriptive test. Ten trained panellists from the Central Lab Complex, Department of Dairy Technology,  participated in the evaluation; all had experience of standardized tests for olfactory and taste sensitivities as well as verbal abilities and creativity. They evaluated 30 g portions of each probiotic yoghurt sample and used a quality rating score card for evaluation of colour (nine points), flavour (nine points), taste (nine points) and texture (nine points) as described by Rogers ; The hig® 9.1 software [Data analysis were performed by two-way analysis of variance technique using the SASsoftware . The difThe most common naturally available phenolics are flavonoids due to their wide range of biological and biochemical activities. The real antioxidant potential is often more precisely exposed by presenting the activity of antioxidant in forms of total flavonoids and phenolics. TPC and TFC in APPE of different apple cultivars are shown in p < 0.05). The initial viable counts of L. bulgaricus, S. thermophilus, B. lactis and L. acidophilus were similar in all yoghurt samples, which revealed non-significant effects (p > 0.05) at day 1 (p < 0.05). The results revealed that at day 1, CTL had the viable count of S. thermophilus 10.63 log cycle, after 21 days the loss in viability was 2.85 log cycle, whereas with APPE 1%, 2%, 3%, 4%, and 5% fortification these losses were 1.67, 1.48, 1,24, 0.79 and 0.47 log cycles, respectively after 21 days. The results revealed that AE1 had less loss of S. thermophilus 1.67, followed by AE2 0.47 log cycle, respectively after 21 days. The initial count of L. bulgaricus was 10.24 log cycle and after 21 days the loss in viability was 2.64 log cycle in control sample whereas with APPE 1%, 2%, 3%, 4%, and 5% fortification these losses were 1.90, 1.25, 1.05, 0.74 and 0.36 log cycles, respectively. In the former study [Streptococcus and Lactobacillus in yoghurt. Some unfavorable impacts of phlorizin and chlorogenic acid on Lactobacillus were observed. Addition of APPE before incubation found in a more uniform distribution of Lactobacillus and Streptococcus as well as uneven distribution was reported in the control. Outcomes of all microbiological characteristics in probiotic yoghurt throughout 21 days at 4 °C presented significant effects . The maximum viability loss of the four microbes were observed in control yoghurt sample for 21 days significantly (p < 0.05). The slight decrease of viable count was perceived in all yoghurt samples with fortification of APE during refrigerated conditions. It was previously studied that, the addition of APPE had a significantly positive impact on the viability of B. lactis and L acidophilus strains [L. acidophilus more than either of the tested polyphenols, except for rutin. The initial count of These outcomes confirm the potential use of APPE as a source of polyphenols to boost the functionality of probiotics in dairy products furthermore to add value to this waste stream agro-industrial material . Nutritip > 0.05). Yoghurt samples with APPE had slightly high levels of total solid contents than the control. The results revealed that CTL had the low TS contents 14.44%, followed by AE1 14.56% while, AE5 had the high TS contents 14.96%, then non-significant difference observed during storage  in TS and milk fat contents among yoghurt samples. It was observed that at day 1, CTL had the high pH values 4.56, followed by AE1 4.51 while, AE5 had the low pH 4.36, then significantly (p < 0.05) decreased to 4.19, 4.13 and 4.02, respectively, for 21 days. The results revealed that the APPE slightly decreased the pH values of yoghurt as compared to control sample. Gurkan et al. [p < 0.05) increased to 1.09, 1.11 and 1.25 respectively for 21 days  decreased to 46.67%, 52.33% and 60.41%, respectively, after 3 weeks (p < 0.05) decreased to 1166 cp, 1253 cp and 1664 cp, respectively, after 3 weeks (p < 0.05) reduced throughout storage [The outcomes revealed that WHC of CTL was 53.67%, followed by AE1 56.10% while, the high WHC of AE5 was 66.23%, then significantly ( 3 weeks . It was  3 weeks . It was  3 weeks . Results storage .p < 0.05) increased TPC  respectively as compared to control yoghurt (1.48 g GAE/100g of DW) on 1 day. The results showed that TPC values were increased from day 1 to 2 weeks but decreased from two weeks to three weeks. The results showed that the total phenolic contents were statistically correlated to the total antioxidant activity of apple peels. Chinnici et al. [Free radicals and reactive oxygen are critical in various illnesses such as, arthritis, atherosclerosis and cancer . The resi et al.  also comi et al. .p < 0.05) the antioxidant activities in AE1, AE2, AE3, AE4 and AE5 compared to respective control yoghurt sample (27.13 ± 1.53%). Polyphenol compounds were antioxidants that had a positive effect on preventing oxidation [Oxidative destruction can affect the flavor, bioactive compounds, destruction of nutrients, and generation of potentially toxic oxidation products . APPE adp > 0.05) between the control and yoghurt enriched with APPE during storage. It was observed that AE3 sample got the best score of taste and color attributes as compared to others followed by the AE4, AE5, AE2 and AE1. The addition of APPE had a significant effect on the taste of probiotic yoghurt. The probiotic yoghurt samples were found to be sweeter and more aromatic by the panelists, due to the acidic and sweet taste of the apple peel extract. It was concluded that AE4 and AE5 samples had fruity flavor as compared to AE3, AE2 and AE1, while the lowest scores were obtained by the CTL significantly (Taste, flavor, color, and texture properties of probiotic yoghurt were evaluated as sensory attributes, shown in ficantly . The lowB. lactis and L. acidophilus and fortified with APPE—proved to be an acceptable probiotic milk product. This APPE as prebiotic ingredient had viable counts greater than the minimum requirement to be considered probiotic. Notably, APPE had the highest viable counts throughout fermentation and 21 days of refrigerated storage. It was concluded that the survival of probiotics and antioxidant activity of yoghurt were enhanced with the addition of APPE. Probiotic yoghurt fortified with APPE can act as natural source of high-quality antioxidant and bioactive compounds. Nevertheless, addition of APPE did not lead to the substantial disruption of texture and flavor, showing an excellent sensory quality of probiotic yoghurt after 21 days of storage. Yoghurt—fermented with Hence, it can be concluded that the addition of APPE in probiotic yoghurt gives a functional product with very good sensory and physical characteristics. Besides, this research has demonstrated that APPE could provide adequate protection of probiotic bacteria during production and storage of yoghurt. The present study provides grounds for further investigation on the possibility of using apple peels as a prebiotic for the survival of probiotic bacteria in food products, where it may be regarded as an alternative way of supplying probiotics to consumers.


Riociguat is approved for pulmonary arterial hypertension and has antiproliferative, anti-inflammatory and antifibrotic effects in animal models of tissue fibrosis. We evaluated the efficacy and safety of riociguat in patients with early diffuse cutaneous systemic sclerosis (dcSSc) at high risk of skin fibrosis progression.In this randomised, double-blind, placebo-controlled, phase IIb trial, adults with dcSSc of <18 months' duration and a modified Rodnan skin score (mRSS) 10–22 units received riociguat 0.5 mg to 2.5 mg orally three times daily (n=60) or placebo (n=61). The primary endpoint was change in mRSS from baseline to week 52.At week 52, change from baseline in mRSS units was –2.09±5.66 (n=57) with riociguat and –0.77±8.24 (n=52) with placebo ). In patients with interstitial lung disease, forced vital capacity declined by 2.7% with riociguat and 7.6% with placebo. At week 14, average Raynaud’s condition score had improved ≥50% in 19 (41.3%)/46 patients with riociguat and 13 (26.0%)/50 patients with placebo. Safety assessments showed no new signals with riociguat and no treatment-related deaths.Riociguat did not significantly benefit mRSS versus placebo at the predefined p<0.05. Secondary and exploratory analyses showed potential efficacy signals that should be tested in further trials. Riociguat was well tolerated. There is a need for new therapies for patients with diffuse cutaneous systemic sclerosis (dcSSc).The soluble guanylate cyclase stimulator riociguat has antiproliferative, anti-inflammatory and antifibrotic effects in vitro and in animal models of tissue fibrosis and has been shown to increase digital blood flow in patients with Raynaud’s phenomenon.Systemic Sclerosis study failed to meet its primary endpoint of change in modified Rodnan skin score after 52 weeks at p=0.08. However, some secondary and exploratory endpoints showed potential efficacy signals that should be investigated in further trials. Riociguat was well tolerated, with no unexpected safety signals.The RIociguat Safety and Efficacy in patients with diffuse cutaneous Although the primary endpoint was not significant, this phase IIb study provides important information that can inform future study design and gave preliminary findings that could be explored in future trials in patients with dcSSc.Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterised by fibrosis, inflammation and microvascular injury.The soluble guanylate cyclase (sGC) stimulator riociguat increases intracellular cyclic guanosine monophosphate (cGMP).Systemic Sclerosis (RISE-SSc) trial compared riociguat with placebo in patients with early dcSSc.We hypothesised that riociguat may benefit tissue fibrosis in dcSSc. The RIociguat Safety and Efficacy in patients with diffuse cutaneous RISE-SSc  ≥40% at screening. Patients receiving concomitant nitrates, nitric oxide donors, phosphodiesterase inhibitors or recent SSc therapies were excluded  classification criteria for SSc,uded see .Patients were randomised 1:1 to riociguat or matching placebo, individually adjusted every 2 weeks from 0.5 mg to 2.5 mg orally three times daily over 10 weeks and continued throughout the treatment phase. From week 26, rescue therapy was permitted at investigator discretion see . PhysicaThe primary endpoint was the change in mRSS from baseline to week 52. To prevent interobserver variability, the same physician, experienced in skin scoring, scored the same patient throughout the study. Skin fibrosis was also analysed by prespecified exploratory analyses of mRSS progression (increase by >5 units and ≥25% from baseline) and regression (decrease by >5 units and ≥25% from baseline). This definition was based on analyses suggesting that a reduction in mRSS of 3.2–5.3 units or 15%–25% from baseline is considered a minimally clinically important difference.CO% were assessed overall and (post hoc) in patients with ILD according to medical history and restrictive lung disease (FVC% 50%–75% at baseline).FVC% and DLEffects on RP at week 14 versus day 0 and net digital ulcer burden were prespecified exploratory analyses. For details of other prespecified exploratory analyses and post hoc assessments see Assuming a standard deviation (SD) of 8 mRSS units,10.1136/annrheumdis-2019-216823.supp3Supplementary dataPatients were not directly involved in the design, recruitment or conduct of the study.In total, 121 patients were randomised . The study was completed according to the protocol. Five patients in each group received ≥1 new rescue therapy after week 26. Study discontinuation occurred in 18 (30.0%) riociguat-treated patients and 15 (24.6%) placebo-treated patients . At weekThe primary endpoint was not met at the predefined p<0.05. At week 52, mean mRSS was 14.63 (SD 6.56) with riociguat versus 15.73 (SD 10.48) with placebo: difference of least squares (LS) means –2.34 (standard error (SE) 1.33); 95% confidence interval (CI) –4.99 to 0.30; relative difference –14%; p=0.0815. At week 52, the mean change from baseline in mRSS was –2.09 (SD 5.66) with riociguat and –0.77 (SD 8.24) with placebo . ProgresOn subgroup analyses, the change in mRSS with riociguat versus placebo showed a nominal p value <0.05 for mRSS 17–22, anti-RNA polymerase III positive/SCl-70 negative, baseline FVC 50%–75% and high-sensitivity C-reactive protein >3.0 mg/L see .ACR CRISS as a measure of improvement did not show significant differences in this trial designed for prevention of worsening. Eighteen per cent of patients in each group had a CRISS improvement probability score ≥0.60 ). However, in step 1 of the CRISS analysis, 1 (1.7%) patient in the riociguat group versus 4 (6.6%) in the placebo group met the definition for SSc-related organ involvement. Other secondary endpoints are shown in Overall, the change in FVC% between baseline and week 52 was −2.38% (SD 7.52) with riociguat and −2.95% (SD 9.73) with placebo (difference of LS means −0.20 (SE 1.61); 95% CI −3.40 to 3.00; nominal p=0.901; CO% decreased by −2.31% (SD 10.08) with riociguat and −4.09% (SD 12.19) with placebo (difference of LS means 2.01 (SE 2.14); 95% CI −2.24 to 6.25; nominal p=0.3502). In patients with ILD by medical history the changes in DLCO% were –4.55 (SD 8.12) with riociguat (n=11) and –7.63 (SD 13.37) with placebo (n=12). In those with baseline FVC% 50%–75%, DLCO% increased by 2.26 (SD 15.16) with riociguat (n=8) and fell by –7.32 (SD 17.24) with placebo (n=5).DLAt baseline, 9 (15.0%) patients had DUs in the riociguat group versus 6 (9.8%) in the placebo group. New DUs were reported in 2 (3.3%) patients in the riociguat group and 6 (9.8%) in the placebo group at week 14, and in 5 (8.3%) patients and 12 (19.7%) patients, respectively, at week 52. There were 4 and 26 new DUs with riociguat and placebo, respectively, at week 14; and 12 and 72 new DUs, respectively, at week 52 see . ConcomiFindings from prespecified exploratory analyses and post hoc assessments are provided in Overall, 58 (96.7%) patients in the riociguat group and 55 (90.2%) in the placebo group experienced an AE see . Most AEOf those with ILD by medical history, AEs were reported in 10 (83.3%)/12 patients with riociguat and 12 (92.3%)/13 patients with placebo. AEs reported more frequently with riociguat than with placebo were predominantly dizziness and gastrointestinal events see . The incRISE-SSc investigated the effects of riociguat on disease progression in patients with early dcSSc. mRSS was selected as the primary endpoint as it correlates with biopsy measures of skin thickness and reflects disease prognosis and visceral involvement.There are several potential reasons why the primary endpoint was not met in this study. First, RISE-SSc was designed to detect a placebo-adjusted change of mRSS between riociguat and placebo with 80% power. For the low baseline mRSS expected in this study, a 4-unit change would represent a change of 23%. The between-groups difference was 2.3, which was less than expected. This low treatment effect was probably the main reason why the primary endpoint was not met. In addition, the higher than expected numbers of skin fibrosis regressorsAs expected, the combined secondary endpoint did not favour riociguat because the ACR CRISS evaluates disease improvement, whereas RISE-SSc was designed to detect prevention of progression. ACR CRISS is not expected to be positive in such a trial design.Some measures of mRSS, lung function in patients with evidence for pre-existing ILD and the prevention of new DU and RP symptoms suggest potential signals for efficacy. It is important to note that the descriptive analyses of predefined secondary and exploratory endpoints should not be interpreted as efficacy of riociguat, but as a potential signal that can be investigated in further studies.AEs reported more frequently with riociguat than placebo were mainly gastrointestinal events, dizziness or peripheral oedema. These events are consistent with the effects of riociguat, such as relaxation of smooth muscle cells in the vasculature (often associated with blood pressure decrease) or the gastrointestinal tract and did not increase the incidence of withdrawal due to AEs. SAEs were less common with riociguat than with placebo, no riociguat-treated patient experienced an SAE considered related to study treatment, and fewer discontinued study medication because of an SAE with riociguat than with placebo. Riociguat was, therefore, well tolerated in early dcSSc, particularly when compared with traditional immunosuppressive agents.Discontinuation rates (≈30% with riociguat and ≈25% with placebo) were higher in RISE-SSc than with active treatment in recent trials of abatacept (23%)In conclusion, RISE-SSc failed to meet its primary endpoint and is therefore a negative trial. However, it provides important findings for the identification of patients at high risk of skin fibrosis progression that could inform future studies in patients with dcSSc. In addition, there are potential efficacy signals in early dcSSc and these may be explored further with additional randomised controlled trials.


Significant gender differences have been found in the performance of exercise ECG for the identification of coronary artery disease. Our aim was to evaluate possible differences in the diagnostic power of cardiac MRI using SSFP-Perfusion under adenosine related vasodilatation in both gender subgroups in a large consecutive cohort of patients with suspected CAD.228  patients with suspected CAD were examined with MRI (1.5 T Intera CV) and coronary angiography. A 3-slice short axis SSFP perfusion scan with a saturation prepulse before each slice was performed during infusion of adenosine and at rest followed by myocardial scar imaging. Gadolinium – DTPA was given at 0.1 mmol/kg body weight. Images were assessed visually by two observers in a joint reading.Sensitivity, specificity and accuracy of MRI first-pass perfusion for detection of a coronary artery stenosis  on a per patient basis were 92,3%, 81,6% and 90.0% in the male subgroup and 97,7%, 94,4% and 95,8% in the female subgroup. The results for detection of a significant lesion  were 96.0%, 68,5% and 87,8 in the male subgroup and 96,3%, 80,9% and 89,6% in the female subgroup.In contrast to data from stress ECG, MRI adenosine fist-pass perfusion analysis using a SSFP sequence reveals no differences regarding diagnostic performance in female compared to the male group in our cohort.


Glioma-associated oncogene homolog 1 (GLI1) as a biomarker to assess the extent of Hedgehog pathway inhibition by sonidegib in patients with locally advanced BCC (laBCC) and metastatic BCC (mBCC). The study enrolled 230 patients, 79 and 151 receiving sonidegib 200 and 800 mg QD, respectively. At week 17, GLI1 expression was reduced from baseline by a median percentage  of 88.7% (54.6%–93.0%) and 97.0% (77.5%–98.9%) for aggressive laBCC, 97.5% (80.3%–98.8%) and 95.0% (80.7%–97.5%) for nonaggressive laBCC, and 99.1% (96.4%–99.6%) and 99.3% (95.9%–99.9%) for mBCC in the 200 and 800 mg groups, respectively. Substantial repression of GLI1 was observed in patient subgroups stratified by age, sex, BCC cytological subtype, Eastern Cooperative Oncology Group performance status, lesion site, baseline number of BCCs, and prior radiotherapy. Results support further studies on the inhibition of Hedgehog pathway genes by sonidegib in patients with laBCC and mBCC.The pivotal BOLT  study established the durable efficacy and manageable toxicity of sonidegib 200 mg once daily (QD) through 42 months in patients with advanced basal cell carcinoma (BCC). This secondary analysis used expression of  Basal cell carcinoma (BCC) is the most common skin malignancy, affecting more than 10 million new patients annually worldwide and with an incidence that increases by approximately 1% each year . Most BCPatched 1 (PTCH1) and Smoothened (SMO) ) were assessed through 42 months of treatment in patients with advanced BCC in the Basal cell carcinoma Outcomes with LDE225 (sonidegib) Treatment (BOLT) study (NCT01327053) –18. The Overall, 230 patients were enrolled in the study, of whom 79 and 151 were randomized to sonidegib 200 and 800 mg QD, respectively . At the time of data cutoff for biomarker analysis (6 months), 39 (49.4%) patients in the 200 mg group and 46 (30.5%) patients in the 800 mg group were still receiving treatment. The biomarker population included 67 and 83 patients randomized to sonidegib 200 and 800 mg QD, respectively. AEs were the most common reason for discontinuation, reported for 16 (20.3%) and 48 (31.8%) discontinuing patients in the 200 and 800 mg group, respectively.Patient demographics and clinical characteristics were similar between the biomarker and intent-to-treat (ITT) populations (Supplementary Table 1). The biomarker population was 62.7% and 65.1% male with mean (standard deviation [SD]) age of 65.6 (15.6) and 64.0 (14.9) years for the 200 and 800 mg groups, respectively. The ITT population was 60.8% and 63.6% male with mean (SD) age of 65.6 (15.7) and 63.6 (14.6) years for the 200 and 800 mg groups, respectively. Patients with laBCC comprised 91.0% and 91.6% of the biomarker population, and 83.5% and 84.8% of the ITT population for the 200 and 800 mg groups, respectively.GLI1 expression at baseline was −2.64  and −3.04  for 200 and 800 mg groups, respectively. Longitudinal analyses showed substantial reductions in GLI1 expression from baseline. Expression was reduced by a median (95% CI) of 87.4% (77.0%–96.1%) and 96.2% (94.1%–98.4%) at week 9, 92.7% (78.4%–96.8%) and 95.8% (91.8%–98.2%) at week 17, and 93.0% (33.1%–97.6%) and 97.1% (87.8%–99.5%) at the end of treatment (EOT) for the 200 and 800 mg groups, respectively .Median (95% CI) GLI1 expression at week 9 was 87.4% (55.6%–96.9%) and 94.2% (87.8%–98.4%) for patients with aggressive laBCC, 86.7% (80.8%–96.1%) and 97.2% (95.0%–98.9%) for patients with nonaggressive laBCC, and 98.2% (85.1%–98.5%) and 99.2% (94.3%–99.6%) for patients with mBCC receiving sonidegib 200 and 800 mg QD, respectively (GLI1 expression at EOT was 96.0% (67.9%–98.9%) and 98.0% (90.6%–99.7%) for patients with aggressive laBCC, 73.0% (49.5%–98.9%) and 92.5% (40.5%–99.8%) for patients with nonaggressive laBCC, and 77.0% (56.8%–97.3%) and 96.1% (22.6%–99.7%) for patients with mBCC receiving sonidegib 200 and 800 mg QD, respectively.When patients in the 2 dose groups were stratified by the type of BCC, median (95% CI) reduction in ectively . At weekGLI1 expression from baseline was overall consistent between subgroups of patients with laBCC and mBCC stratified by demographic , with median percent reduction ranging 74.5%–97.9% and 95.7%–98.0% at week 9, and 90.8%–99.5% and 96.1%–97.0% at week 17, for the 200 and 800 mg groups, respectively (Supplementary Table 2). However, a significant association was not observed between strength of GLI1 repression and odds of tumor response (CR+PR), with hazard ratio  for low vs high tumor inhibition of 1.4  and 0.8 , for the 200 and 800 mg groups, respectively (Supplementary Table 3).Substantial reductions in GLI1 inhibition and time to tumor response (TTR), with HR  for low vs high expression of 0.9  and 1.4  for the 200 and 800 mg groups, respectively (Supplementary Table 4).Overall, no significant association was observed between extent of GLI1 inhibition and time to onset of grade ≥ 2 creatine kinase (CK) elevation, with HR  for low vs high expression of 0.6  and 1.2  for the 200 and 800 mg groups, respectively (Supplementary Table 5). Among patients with greater GLI1 inhibition from baseline, those in the 800 mg dose group had an increased risk of grade ≥ 2 CK elevation, with HR  vs the 200 mg dose of 2.3 .There was no overall significant association between extent of GLI1 levels from baseline across doses, BCC subtypes, examined time points, and demographic and baseline disease characteristics in patients with advanced BCC. Marked reductions in GLI1 levels from baseline were observed in patients who achieved disease control with sonidegib, consistent with Hedgehog pathway inhibition.Results from this secondary analysis suggest that sonidegib treatment led to substantial reductions in PTCH1 [SMO—sonidegib’s target in the pathway—to dissociate from PTCH1 and migrate to the primary cilium, where it releases the cytoplasmic sequestration of the GLI family of transcription factors by Suppressor of Fused through a multistep signaling cascade [GLI1 activation have also been reported, including by the Ras and p53 families of tumor suppressors [GLI1 activation promotes tumor growth, migration, and angiogenesis [The Hedgehog pathway plays a key role in regulating cell proliferation and differentiation during development and is involved in the maintenance and repair of many adult tissues including the skin, hair, muscles, and nervous system . Upon acPTCH1 . This ca cascade . Noncanopressors . Aberranogenesis .GLI1 suppression is dose- and exposure-dependent, a reduction of GLI1 expression did not always correlate with tumor response in the phase 1 efficacy and safety study for sonidegib, most likely due to limited sample size, indicating resistance may develop despite GLI1 inhibition [GLI1 expression in this biomarker analysis is consistent with the possibility that patients with low GLI1 inhibition are resistant to sonidegib. However, there was no significant correlation between sonidegib efficacy and the strength of GLI1 inhibition. This is possibly due to the study not being sufficiently powered to confirm this correlation. Additionally, inhibition of GLI1 in the different patient subgroups examined was uniformly strong, and none of the examined demographic and baseline clinical characteristics showed strong correlation with sonidegib resistance.Despite the overall durable efficacy of sonidegib treatment observed in the BOLT study, a subset of patients develop resistance to HHIs that can be either primary or acquired after initial response to treatment . Moreovehibition . The strGLI1, GLI2, PTCH1, and PTCH2 messenger ribonucleic acid (RNA) and protein, as well as GLI1 and GLI2 translocation into the nucleus [GLI1 and GLI2 inhibition by RNA interference revealed the effect of sonidegib on Hedgehog pathway downstream targets, including upregulation of the cell death mediators, Fas, Death receptor (DR)4, and DR5, and downregulation of the cell proliferation mediators B-cell lymphoma 2 and Platelet-derived growth factor receptor A [GLI1 and GLI2 and reduced cell proliferation in combination with everolimus or sunitinib, whereas direct inhibition of GLI1 and GLI2 in combination with everolimus or sunitinib had no impact on proliferation, suggesting that other targets downstream of SMO may play a role in tumor response [Animal and cell-line cancer models studied the impact of sonidegib on Hedgehog pathway activity. In human primary glioblastoma initiating cells, sonidegib reduces levels of  nucleus . Epistasceptor A . In humaresponse .GLI1 inhibition and time to onset of grade ≥ 2 CK elevation—suggesting that CK elevation is not influenced by the extent of GLI1 inhibition. CK elevation is a common treatment-emergent AE observed in patients treated with Hedgehog inhibitors. While the exact mechanism responsible for muscle spasms and increased CK levels in patients receiving HHIs is not completely understood, muscle spasms are considered to be linked with paradoxical activation of the SMO/calcium/AMP-activated protein kinase axis, and the inhibition of SMO signaling leads to an influx of calcium into muscle cells [®, Genentech, South San Francisco, CA), an HHI indicated for the treatment of advanced BCC, did not include CK monitoring; however, muscle spasms were reported in 71.2% of patients [This analysis found no significant association between the magnitude of le cells . The pivpatients . All curP-values were nominal or were adjusted for multiplicity only at the biomarker level within a specific model or analysis. GLI1 was the only examined biomarker, and data on the expression of other prominent members of the pathway were not collected. Additionally, GLI1 expression as related to reduction in tumor mass was not directly evaluated in this analysis. Subsequently, decreases in tumor size may have contributed to reductions in GLI1 levels measured following treatment.Limitations of the current study include the lack of statistical power to assess specific biomarker-related hypotheses. All biomarker analysis should be considered exploratory and hypothesis-generating, and all GLI1 expression is consistent with potent inhibition of the Hedgehog pathway by sonidegib in patients with laBCC and mBCC. These results support further clinical studies on the impact of sonidegib on Hedgehog pathway biomarkers.In summary, the reduction of This randomized, double-blind, adaptive phase 2 multicenter study adhered to the ethical principles of the Declaration of Helsinki and received approval for its protocol and all amendments from an Independent Ethics Committee or Institutional Review Board at each study site. Written informed consent was obtained from all patients before any study-specific procedures.Study design is described in detail elsewhere and is briefly summarized here and in Supplementary Figure 2. The study enrolled men and women age ≥ 18 years with a histologically confirmed diagnosis of mBCC or laBCC  and a World Health Organization (WHO) performance status ≤ 2. Patients were randomized 1:2 to receive sonidegib 200 or 800 mg QD until disease progression, unacceptable toxicity, withdrawal of consent, study termination, or death.Tumor response was evaluated with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for patients with mBCC. For laBCC, the standard RECIST 1.1 criteria are inadequate, since posttreatment morphological changes such as ulceration, cyst formation, and scarring may confound tumor response evaluation. A modified (m)RECIST protocol was developed to assess tumor response in laBCC, integrating central histological review, one-dimensional localized soft-tissue magnetic resonance imaging (MRI) along the lesion’s longest diameter per RECIST 1.1, and bidimensional color photography measurements per WHO guidelines.The primary efficacy endpoint was ORR per central review. Secondary efficacy assessments included TTR and best overall response . Best overall response was assessed by central review according to mRECIST in patients with laBCC and RECIST 1.1 in patients with mBCC. mRECIST criteria includes a combination of MRI scans, color photography, and baseline and follow-up histopathology data for patients to assess tumor response.Safety assessments included AEs monitored throughout the study, coded using the medical Dictionary for Regulatory Activities version 19.0, and assessed for toxicity using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. CK levels were assessed prior to starting treatment or within 72 hours of the first dose, then weekly during the first 2 months, and every 4 weeks thereafter while on study treatment.Biopsies were collected from accessible lesions at Screening, weeks 9 and 17 predose, and within 21 days after the last dose of study drug. For patients with multiple lesions, no specific lesion was designated for biopsy, and any lesion could be used. Presence of tumor tissue in biopsy samples was histologically confirmed prior to biomarker analysis.GLI1 expression at Screening was used as baseline measurement. Gene expression at all examined time points was assessed using reverse transcriptase polymerase chain reaction, in terms of the number of reaction cycles needed to reach the threshold amount of product. Expression of GLI1 at each time point was normalized to the housekeeping gene ubiquitin C, and fold and percent change from baseline of normalized GLI1 expression were computed.GLI1 expression was stratified by type of BCC (aggressive and nonaggressive laBCC and mBCC), age, sex, number of lesions at baseline, cytology subtype, primary site of cancer, prior radiotherapy, and Eastern Cooperative Oncology Group performance status. Association between GLI1 expression and select efficacy and safety assessments was evaluated, including best overall response, TTR, and time to onset of grade ≥ 2 CK elevation.Percent change from baseline in GLI1 expression. Since inhibition of the Hedgehog pathway with sonidegib should result in GLI1 inhibition, postbaseline records with > 100% change in GLI1 levels from baseline were considered outliers and were excluded from analyses and models.The ITT population included all randomized patients. The subset of the ITT population with valid biomarker samples comprised the biomarker population used for all biomarker analyses. Data collected up to 6 months after the last patient randomization date were included in the analysis. All statistical evaluations were exploratory since the study was not powered to assess specific hypotheses regarding change in GLI1 levels or changes from baseline in GLI1 levels and clinical efficacy outcomes. Percent change in GLI1 levels was summarized using descriptive statistics . Longitudinal analyses of GLI1 expression were performed using a linear mixed model, including fold change in GLI1 expression from baseline as a response variable and visit, treatment group, and visit-by-treatment interaction as covariates. Median percent change from baseline and 95% CI for each dose group and time point were computed based on model-based least squares mean fold change estimates.Visual assessments of strip plots determined the relationship between baseline GLI1 levels or changes from baseline in GLI1 levels, and TTR and time to onset of grade ≥ 2 CK elevation. Kaplan-Meier curves and log-rank test–based P-values for the difference in time-to-onset curves were produced for groups defined by dose level and categorized GLI1 levels. Normalized baseline GLI1 levels were categorized as low or high based on the median (both doses combined). Percent change in GLI1 from baseline at week 9 or 17 was categorized as low (greater inhibition) or high (lesser inhibition) based on the third quartile (both doses combined).Cox proportional hazards models determined associations between baseline


Airborne particulates are an issue in many urban regions around the world and their detrimental impact on human health has increasingly become a public health concern.The aim of the present study was to examine particle pollution in an urban settlement in Nigeria. This study examines the extent, spatial variation, and sources of indoor and outdoor particulate matter (PM) concentrations in Ogbomoso, Nigeria.1, PM2.5 and PM10) within/around each building were measured with a particle counter and details on domestic utilities/practices were obtained with a questionnaire. Analysis of variance was used to determine inter-zonal variations in PM levels and simple linear regression was used to analyze the relationship between indoor and outdoor air quality.The survey research method was adopted. Sampling included 385 buildings across selected precincts and different residential zones in the town of Ogbomoso. Particulate matter analytes (PM2.5) concentrations were lower than the World Health Organization (WHO) Interim Target limit of 75 μg/m3, while concentrations of inhalable particles (PM10) were higher than the set limit of 150 μg/m3 for daily averages. Coarse particles dominated, with an accumulative PM2.5/PM10 ratio of 0.24. The inter-zonal analysis of PM concentrations revealed that indoor and outdoor PM levels varied significantly by residential zone . Regression analysis showed a significant but weak relationship between indoor and outdoor PM levels (r = +0.221), while the coefficient of determination (R2 = 0.049) showed that only about 5% of the variation in indoor air quality was associated with outdoor air quality. Particle pollution inducers were identified in the residents' waste disposal methods and adopted fuels/energy sources, with firewood and charcoal linked with increased concentrations of particulate matter.Indoor and outdoor respirable particle (PMAir quality was relatively poor in the study area given observed particulate matter concentrations. Cleaner fuels, effective waste management systems and improved roads are needed to foster better air quality in the study area.The authors declare no competing financial interests Air pollution has been a serious environmental problem for many years and is becoming a greater issue globally. Particulate matter in ambient air presents a risk to human health, particularly after prolonged exposure. Air quality problems are experienced in both developed and developing countries and epidemiological studies have demonstrated correlational and causal relationships with various ailments. The International Agency for Research on Cancer (IARC) revealed that worldwide 223,000 lung cancer deaths in 2010 resulted from air pollution.25 This problem is even greater in developing countries. According to the World Health Organization (WHO), more than two-thirds of the global estimates of mortality from indoor air pollution occur in Southeast Asia and sub-Saharan Africa.Both indoor and outdoor air pollution present a major challenge, although studies often show mortality from indoor air pollution to be twice that of outdoor air pollution.Within residential environments, ambient particulate matter (PM) is a useful measure of air quality. Particulate matter includes a wide variety of substances including dust, pollen, dander, airborne smoke, and soot as well as liquid droplets from fuel combustion.There is a growing need for empirical investigations into indoor and outdoor air quality with regard to airborne particulates. Few such studies have been conducted in developing countries. Air quality studies in Nigeria often address either indoor air quality in rural areas or outdoor air quality in industrialized regions, addressing primarily solid fuel use in the former and vehicular/industrial emissions in the later. There have been few studies set in residential urbanizing settlements and still fewer exploring differences between indoor and outdoor air quality. The present study examines air quality in Ogbomoso, Nigeria and provides insight into the extent, spatial variation and interconnection between indoor and outdoor air quality.10 (coarse particles less than 10 μm), PM2.5 (fine particles less than 2.5 μm) and PM1(ultrafine particles between 0.1 and 1 μm), and their health implications are well documented. The fine particles of PM2.5 (respirable particles) pass through the nose and are deposited in the windpipe or lungs, where as PM10  are deposited on the hairs in the nose or at the bends of the nasal passages; both are causal factors for respiratory and cardiovascular morbidity.2.5 is a stronger risk factor for mortality than PM10, while PM1 which is smaller in size, is considered more harmful than both as it is likely to reach deeper into the respiratory system carrying with it more toxins from anthropogenic emissions.13Particulate matter is used to describe condensed phase (solid or liquid) particles suspended in the atmosphere and it is categorized by size, specifically by aerodynamic diameter in microns (millionths of a meter).CPMagCumulative particulate matter aggregateI/OIndoor/outdoorPMParticulate matterWHOWorld Health Organization14 Diesel exhaust—a major contributor to PM pollution—has been linked to acute vascular dysfunction and increased thrombus formation.2.5) is estimated to be responsible for about 3% of adult cardiopulmonary disease mortality; about 5% of trachea, bronchus, and lung cancer mortality; and about 1% of mortality in children from acute respiratory infection in urban areas worldwide. According to Cohen et al., this amounts to about 0.8 million (1.2%) premature deaths and 6.4 million (0.5%) lost life years.4Long term exposure to particulate matter has been linked with acute respiratory morbidity in the form of pneumonia and asthma.3 and 98 μg/m3 in sixteen Niger Delta communities, exceeding the World Bank standards for annual mean.10 mass loads exceeded the WHO set limits, with the exception of Abuja, while Aba had the highest PM10 concentration levels.Recently, studies in Nigeria have explored the extent of PM pollution. Particulate loads have been found to range between 40 μg/m.The present study took place in Ogbomoso, an urbanizing town in southwestern Nigeria, and covered Ogbomoso North and Ogbomoso South Local Government Areas in 2016. With an estimated population of 354,617,.Following the design of a previous study, “Intra-urban pattern and determinants of indoor air quality in Ogbomoso, Nigeria”Supplemental Material). from the core, transition and suburban zones, respectively, were sampled and data collected over a period of four weeks during the rainy season. In each building, a questionnaire was administered to an adult resident and the GT-531 mass particle counter  was used for PM data collection. Consent was obtained for the survey in buildings as residents were informed of the nature of the study and the safety of the particle counter prior to requests to take air samples and administering the questionnaire 1, PM2.5 and PM10were computed and presented per precinct in 3 and 35.5 μg/m3, respectively. For fine particles, the highest mean indoor reading was 51.4 μg/m3 and highest outdoor reading was 60.5 μg/m3. For coarse particles, the highest mean indoor and outdoor readings were 230.8 μg/m3 and 382.7 μg/m3, respectively. The cumulative mean indoor and outdoor PM1, PM2.5 and PM10 for the study area were 23.6 μg/m3 and 27.7 μg/m3; 41.6 μg/m3 and 46.3 μg/m3; and 175.5 μg/m3 and 188.8 μg/m3, respectively. With regard to PM2.5/PM10 ratio, the cumulative mean for the study area was 0.24  while the indoor/outdoor (I/O) PM ratios for the ultrafine, respirable and inhalable particles were 0.84, 0.90 and 0.92 .The indoor and outdoor mean concentrations for PM. Moreover, 55.6% of the residents used personal gasoline generators and only one-third (32.7%) of the buildings did not have a generator. Almost 70% of the residents  practiced refuse burning and a very small proportion (5.5%) were serviced by garbage collection trucks.Kerosene and charcoal were the dominant forms of cooking fuels, used by 92.5% and 66.0% of the population, respectively, followed by firewood (20.5%), while the least used was sawdust 1, PM2.5 and PM10 were merged into a composite index of cumulative particulate matter aggregate (CPMag) used as a surrogate measure of air quality and then analyzed over the 385 sampling points within the 27 precincts across the 3 residential zones using analysis of variance. 3). Next was the core area with a CPMag of 79.65 μg/m3, while the suburban zone had the lowest indoor CPMag level (68.29 μg/m3). The observed differences in indoor CPMag across the zones were statistically significant with an alpha level of 0.05 . Hence, indoor air quality varied significantly within the residential zones. Tukey HSD post-hoc test further explains the variation. While there was no statistically significant difference between the indoor CPMag of the core area and that of the transition zone [p value = 0.304 (> 0.05)], the indoor CPMag of the suburban zone differed significantly from both [p value = 0.005 (> 0.05)]. Since the suburban zone had the lowest indoor CPMag, the zone therefore had significantly better indoor air quality than the other residential zones.To explore the variation of air quality across the residential zones in Ogbomoso, PM3), followed by the transition zone (81.62 μg/m3), while the suburban zone had the lowest level (69.68 μg/m3). The difference was statistically significant with an alpha level of 0.05 . Hence, outdoor air quality also varied significantly across the residential zones. The Tukey HSD post-hoc test indicated that the outdoor air quality of the suburban zone was significantly better than that of the core area (p = 0.01), while the difference between the mean CPMag scores for suburban and transition zones was not significant [p = 0.06 (>0.05)]. This implies that the suburban zone, although a lower score than the transition area, cannot be said to be significantly better than the transition zone with respect to outdoor CPMag.Variations in the outdoor CPMag are presented in 1, 383 = 19.731; p = 0.0005) and from the regression model , the coefficient of determination (R2) was 0.049.Correlation analysis was used to explain the relationship between indoor and outdoor air quality. It showed a linear relationship between the indoor and outdoor CPMag with a significant positive correlation of +0.221. This correlation coefficient, which was less than 0.49, was weakly positive.2.5) of 41.6±10.1 μg/m3 and 46.3±8.0 μg/m3 respectively, were lower than the WHO Interim Target 1 limit of 75 μg/m3.10), 175.8±54.3 μg/m and 188.8±122.0 μg/m3 respectively, were higher than WHO Interim Target 1 limit of 150 μg/m3 for daily averages. These findings are consistent with findings on PM pollution across six selected major cities in Nigeria where the daily PM10 mass loads also exceeded the WHO prescribed daily limit but the PM2.5values were within the set limit.19As shown in 10 concentration, were established by the Urban Air Quality Management Strategy in Asia, with 0–6 μg/m3 categorized as good; 60–120 μg/m3 as moderate; 121–350 μg/m3 as unhealthy; 351–425 μg/m3 as very unhealthy and greater than 425 μg/m3 as hazardous.10), although not hazardous, can be described as unhealthy. The recorded indoor and outdoor inhalable particles in the study area (175.8 and 188.8 μg/m3) were higher than the set limit, although greater concentrations, higher than 300 μg/m3, have been recorded in Bangladeshi households as well as in Aba, Port Harcourt, and Lagos–all highly industrialized Nigerian cities.29Five air quality levels, based on PM2.5and PM10 levels in 2.5 and PM10, the indoor levels lagged behind, suggesting that outdoor levels of inhalable and respirable particles were higher than the indoor levels. Nonetheless, indoor levels of inhalable particles were higher than the WHO limits and a significant contributor to this was cooking fuel. Most residents use more than one cooking fuel, and cumulatively, kerosene was the dominant cooking fuel used by 92.5% of the population . Charcoal and firewood were reportedly used in 66.0% and 20.5% of homes, respectively. With biomass fuel predominant in the study area, the resulting emissions were a major source of particulate matter and volatile organic compounds.32The mean PM2.5 and PM10 levels exceeded outdoor levels, the trend showed that air pollution in the ambient outdoor environment was generally greater than pollution within buildings. Outdoor PM sources in the study area, typical of urbanizing traditional towns, include vehicle exhausts along roads , indiscriminate open refuse burning and gasoline generator exhausts from residences or commercial establishments, given the erratic power supply.33 Most dwellings were connected by an array of distributors and access roads, of which only 36.9% were tarred . The lack of unpaved roads fosters dust circulation, and hinders efficient road traffic, leading to congestion, vehicle idling and proliferation of exhausts within the environment. Nearly half (40.8%) of residents burn their refuse around their residential premises and one third (29.1%) in communal open dumps , making intermittent dumpsite fumes a common occurrence. Moreover, with 67.3% of buildings using gasoline generators, given the inadequate public electricity supply, generator emissions are widespread, causing noise, oxides of carbon, nitrogen, sulfur, and particulate matter.34Although there were points where indoor PM2.5 and PM10 concentrations both share a similar pattern from the core area to the suburban area. For both, the levels appear to reach their peak in the transition zone and decrease towards the suburban zone. This is especially true of indoor PM10 concentrations which steadily increased in the core area (core 1–4), reached its peak in the transition zone (transition 8) and gradually decreased towards the suburban zone (suburban 25–27). Both the highest levels for indoor PM2.5 (51.4 μg/m3) and outdoor PM2.5 (60.5 μg/m3) were recorded in precincts 8 and 18 of the transition zone, respectively. The highest mean indoor PM10 (230.8 μg/m3) and outdoor PM10 (382.7 μg/m3) levels were similarly recorded in the precincts of the transition zone, which was also the case for ultrafine particles .3) and was statistically different from that of the core (79.65 μg/m3) and transition (83.54 μg/m3) zones. Similarly, the lowest outdoor CPMag was recorded in the suburban zone (69.68 μg/m3) and though not statistically different from the transition zone (81.62 μg/m3), was significantly different from that of the core area (87.52 μg/m3). Consequently, the transition zone had the worst indoor air quality; the core area, the worst outdoor air quality; while the suburban zone has the best general air quality.The spatial pattern of pollution concentrations over a given area depend on the number, type, strength and distribution of various sources, and on the diffusion potential of the atmosphere, as patterns will change somewhat according to prevailing weather conditions. However, the basic underlying pattern of air pollution concentrations over a given area generally remains fairly constant with some areas having generally higher levels than other areas and given a wide enough number of sampling points as in the present study, this pattern can be revealed.Table 5), and according to the chi square analysis, this did not vary significantly across the three zones. Hence, other factors like traffic intensity were most likely responsible for the low outdoor air quality in the core area. The core area, as seen in 10 to 3000 μg/m3.36The results can be further explained by residents' domestic utilities and practices which are presented in 2.5/PM10 ratio for the study area was 0.24 (Table 2). This ratio is useful for identifying emission sources of particulate matter.2.5/PM10 ratio signifies dominance by fine particles, while a low ratio implies dominance by coarse particles. In other words, the higher the PM2.5/PM10 ratio, the lesser dominance of coarse particles. This ratio in Ogbomoso was similar to those of Aba (0.18), Lagos (0.29) and Port Harcourt (0.23).2.5/PM10 ratios in Nigerian cities revealed that the PM size fraction is dominated by coarse particles, a finding further strengthened by the situation in Ogbomoso.2.5/PM10 ratio across the zones was statistically significant at an alpha level of 0.05 both for indoor  and outdoor  environments.The cumulative PM2.5/PM10 ratio of the transition zone was significantly different from that of the core area and suburban zone , while the outdoor PM2.5/PM10 ratio of the suburban zone was significantly different from the core and transition zone . The transition zone (Table 2) had the least indoor PM2.5/PM10 ratio (0.22), while the suburban zone has the highest outdoor PM2.5/PM10 ratio (0.28). Hence, it can be deduced that although coarse particles generally dominate the PM size fraction in Ogbomoso, they are significantly higher in the transition zone's indoor environment and lower in the suburban's zone outdoor environment. This conclusion is further corroborated by the trend observed in Table 8), such activities were likely responsible for the higher levels of coarse particles.The Tukey HSD post-hoc test revealed that the indoor PMTable 3), resulting in ratios of 0.84, 0.9 and 0.92 for PM1, PM2.5 and PM10, respectively. These were considerably low, compared to the average I/O ratios of 3.74, 2.88, and 1.71, respectively, for PM1, PM2.5 and PM10 in urban residential sites of Pakistan.The disparity in indoor and outdoor air quality is often explained by the I/O ratio. The hourly average concentrations in the study area were used to calculate the average I/O ratio  exacerbates the situation. These are dwellings with a long narrow passage separating rows of directly opposite rooms with single widows. This situation, coupled with the poor public power supply, relative absence of mechanical ventilation and in filtration from building cracks or leaks, allows outdoor air pollutants to easily penetrate the indoor environment, which could narrow the I/O ratio. Enquiries into the influence of ventilation systems on indoor particle concentration shows that I/O ratios range from 0.25–0.60 for particles larger than 1 μm (PM2.5 and PM10) in apartments with natural ventilation.Table 3) observed in the study area.It is noteworthy that 53% of the population used sliding windows and side-hung , window types that allow for unobstructed inflow of air 2) was, however, far from 1 , so the resulting regression equation was not useful for making predictions. All the underlying assumptions for regression analysis were met as the studentized residual plot shows a random scatter of the points i.e. independence with a constant spread, thus, constant variance and no values beyond the ±3 SD reference lines (no significant outliers), as seen in There was a weak but significant positive linear relationship between indoor and outdoor CPMag as revealed in the correlation analysis. Indoor PM level increased with outdoor PM level in the study area. The resulting coefficient of determination (R2 in the results implies that outdoor PM aggregate does not explain much of the variability in the indoor PM aggregate. Only 4.9% (≈ 5%) of the total variation in indoor PM aggregate was associated with outdoor PM aggregate. The low R2 (5%) in Ogbomoso was unlike the findings for the German city of Erfurt where the R2 was 86%, showing very strong correlations for indoor and outdoor respirable particles (PM2.5) with outdoor PM2.5 levels explaining most (80%) of the indoor variation of PM2.5.2 value, to suggest that although outdoor PM levels significantly affect indoor levels, indoor activities (domestic heating and cooking) were the major sources of emissions impairing indoor air quality in the study area.Consequently, the low RAir quality is an important factor in safeguarding human health, thus the present study analyzed airborne particulate matter facets , zone-specific facets  and indoor-outdoor facets. Air quality was relatively poor in Ogbomoso, especially with regard to inhalable particles. Only the suburban part of the town had good air quality. While the current situation was not as hazardous as some industrialized cities within and outside the country, PM should be kept from reaching hazardous levels.Given the situation in the study area, appropriate measures are needed to improve air quality, especially indoor air quality. Considering the observed intra-urban variation of PM levels, efforts should be prioritized in the transition zone. While outdoor air pollution affects indoor air quality owing to infiltration and ventilation, indoor activities appear to contribute more to indoor air pollution than outdoor sources. Hence, good indoor air quality is best achieved by dealing with domestic utilities and practices within traditional urbanizing settlements. A good place to begin such efforts would be a shift from the prevalent use of biomass cooking fuels  and personal generator sets to cleaner energy sources. This can be achieved by revitalizing hydroelectricity and improving access to alternatives like liquefied petroleum gas and solar power.Effective waste management is also imperative. Sanitary landfills are a safer and healthier means of refuse disposal and should be adopted, while open dumps should be discouraged, and stringent measures enforced where needed. The transportation system within the city could also be improved by rehabilitating poorly tarred and un-tarred roads to reduce vehicle idling and dust propagation. Most importantly, the inter-city commute of commercial heavy trucks through the town should be rerouted via the outskirts by construction of alternate express ways, like ring roads, to prevent unnecessary traffic congestion within the town. These steps to be taken by local and state governments can mitigate pollutant emissions from domestic and vehicular combustion processes in the study area. It is hoped that the insights provided in the present study will help foster a better understanding and promotion of cleaner ambient air quality in urban areas.


Those with an HbA1c reduction ≥0.5% were considered good responders (n = 24). After the follow-up, good responders exhibited an improvement in the apnea–hypopnea index (AHI: 26-1 (95% IC: 8.6–95.0) vs. 20.0 (4.0–62.4) events/hour, p = 0.002) and in time with oxygen saturation below 90% (CT90: 13.3 (0.4–69.0) vs. 8.1 (0.4–71.2) %, p = 0.002). No changes were observed in the group of non–responders . The percentage of moderate and severe OSA decreased among good responders (p = 0.040). In the wider population, the change in HbA1c correlated positively to decreases in AHI  and negatively to increases in the minimum arterial oxygen saturation . Stepwise multivariate regression analysis showed that baseline AHI and the absolute change in HbA1c independently predicted decreased AHI (R2 = 0.496). The improvement of glycemic control exerts beneficial effects on sleep breathing parameters in type 2 diabetes, which cannot be attributed merely to weight loss. Type 2 diabetes exerts a negative impact on sleep breathing. It is unknown whether a long-term improvement in glycemic control ameliorates this effect. We conducted an interventional study with 35 patients with type 2 diabetes and obstructive sleep apnea (OSA) to explore this. At home, sleep breathing parameters were assessed at baseline and after a 4-month period in which antidiabetic therapy was intensified. Patients who decreased their body mass index ≥2kg/m In recent years, increasing evidence has appeared to support the idea that type 2 diabetes might contribute to the development of sleep breathing disorders characterized by sleep fragmentation and intermittent hypoxia . In factThe amelioration of sleep breathing disorders in patients with type 2 diabetes through better metabolic control has been only partially examined. In a case-control study involving 30 patients with type 2 diabetes and 10 control subjects, a 5-day hospital admission period of glucose optimization achieved a significant reduction in nocturnal oxygen desaturation events . However2 were excluded. In order to shed light on this issue, we present an interventional study aimed at examining whether the improvement of metabolic control during a three-month period in patients with type 2 diabetes leads to significant changes in sleep breathing parameters. To minimize the confounding effect of weight loss, those subjects with a reduction of BMI ≥2.0 kg/mThe study was conducted in accordance with the ethical guidelines of the Helsinki Declaration. The human ethics committee of the Hospital Universitari Arnau de Vilanova approved the study. Informed written consent was obtained from all participants. This prospective interventional study assessed the consequences of improving glycemic control on sleep breathing parameters in subjects with type 2 diabetes without any known pulmonary disease. The study examined a total of 216 consecutive Caucasian subjects with type 2 diabetes at their initial visit to the outpatient Diabetes Clinic from April 2018 to September 2019 .2, HbA1c ≥7.5% (58 mmol/mol), no medical history of lung disease and type 2 diabetes with at least 5 years of follow-up. Among the 145 patients who met the inclusion criteria, we excluded 55 for the following reasons: an inability to understand instructions on how to conduct the study at home (n = 15), unwillingness to participate in the study (n = 14), patients under treatment with continuous positive airway pressure (CPAP) (n = 12), hyperglycemia secondary to corticosteroids (n = 9), active malignancy or malignancy diagnosed within the previous five years (n = 3) and heart failure (n = 2). No pregnant women were included in the study. Finally, a baseline sleep study was performed at home in 90 subjects, and only those with baseline AHI ≥ 5 events/hour and studies with more than 5 hours of data register (n = 68) were invited to repeat the study after a 3-month period, during which antidiabetic treatment was strengthened. Nine patients failed to perform the second evaluation. In addition, to minimize the influence of weight loss on the results, 14 patients who reduced their BMI by more than 2.0 kg/m2 were excluded, as well as 10 patients with less than 5 hours of data registered. In all, 35 patients were included in the study. Those with a reduction of their HbA1c ≥0.5% (arbitrary set point) were considered good responders (n = 24) and the other 11 non-responders, patients. Total body fat and abdominal fat were estimated using the Body Adiposity Estimator (CUN-BAE) and the equation proposed by Bonora et al., respectively [The inclusion criteria included: aged between 40 and 70 years, a BMI lower than 40 kg/mPAP) n = , hypergl2) ≥ 3%. The AHI was characterized as the sum of apneas plus hypopneas recorded during the study per hour of monitoring time. In accordance with the American Academy of Sleep Medicine scoring criteria, obstructive sleep apnea (OSA) was defined as an AHI ≥ 5 events/hour, and patients were divided into non-OSA (AHI < 5 events/hour), mild OSA (AHI between 5 and 15 events/hour), moderate OSA (AHI between 15 and 30 events/hour), and severe OSA (AHI >30 events/hour) [2 levels. The degree of sleepiness was evaluated using the Epworth Sleepiness Scale (ESS), a widely used questionnaire based on the tendency to fall asleep during various daytime situations [All participants underwent an overnight home sleep study using non-attended cardiorespiratory polygraphy  according to standard techniques. The recorded parameters included oronasal flow, thoracoabdominal movements, electrocardiogram and pulse oximetry. A trained scorer blinded to the study reviewed all sleep studies manually. An apnea was defined as a decrease of 90% in pre-event baseline airflow with a duration of at least 10 seconds. Hypopnea was defined as a ≥30% reduction in nasal cannula tracing with respect to baseline with a duration of at least 10 seconds and associated with a drop in arterial oxygen saturation (SaOts/hour) . Five oxtuations . A scoreType 2 diabetes was defined according to the criteria recommended by the Expert Committee on the Diagnosis and Classification of Diabetes . At baseAll subjects underwent treatment intensification to improve glycemic control according to our routine medical practice. At the end of the study, the proportion of patients receiving insulin therapy had increased to 37.8% and 51.4% were treated with GLP-1 receptor agonists (12 of the 18 patients in combination with insulin) and 11.4% were on oral therapy only. None of the subjects remained on treatments comprising only diet or metformin.Fasting plasma glucose ) and HbA1c (chromatography) were obtained from all patients with type 2 diabetes.2 test was used to compare changes in categorical variables between baseline and the end of the follow-up, while a paired Student’s t-test was used to compare non categorical data. The Kruskal–Wallis test and the one-way analysis of variance were used to compare both nonparametric and parametric variables between more than two groups. The relationship between continuous variables was examined by the Pearson linear correlation test. A stepwise multivariate regression analysis was performed to explore the variables independently related to the absolute change of AHI and the minimum SaO2. Variables significantly associated with changes in sleep breathing parameters in the bivariate analysis , together with clinically relevant variables with a potential impact on sleep breathing dysfunction ) and type 2 diabetes chronic complications (baseline HbA1c and known type 2 diabetes duration) were included in the analysis. All “p” values were based on a two-sided test of statistical significance, and significance was accepted at a level of p < 0.05.The SPSS software  was used to perform the statistical analyses. A normal distribution of the variables was established using the Kolmogorov–Smirnov test. Data were expressed as median (range), mean ± SD or as a percentage. The χp < 0.001)  were considered good responders. In this group, HbA1c significantly decreased from 8.8 ± 0.9 to 7.3 ± 0.6 %  . By cont< 0.001) .p = 0.002), CT90 (13.3 (0.4 to 69.0) % at baseline vs. 8.1 (0.4 to 71.2) % at the end of the study, p = 0.002) and ODI 3%   vs. 0.4 (0.0 to 15.0) %, p = 0.093), similar to the group of non-responders.Subjects who exhibited a significant improvement in their metabolic control also revealed a positive and significant impact in their AHI (26.1 (8.6 to 95.0) events/hour at baseline vs. 20.0 (4.0 to 62.4) events/hour at the end of the study, < 0.001) . These cp = 0.040)  . HoweverAt the end of follow-up, 13 patients were under treatment with insulin treatment, 6 were on GLP-1 receptor agonist, and 12 received treatment with insulin plus a GLP-1 receptor agonist. The nocturnal sleep measurements at baseline and after the metabolic improvement period were similar between these three groups . Howeverp = 0.035) and increments in the minimum SaO2 achieved during the nocturnal time   . The oth2 = 0.496) (2 (R2 = 0.288).Finally, the stepwise multivariate regression analysis performed in the entire population with type 2 diabetes showed that baseline AHI together with the absolute change in HbA1c  independently predicted changes in the AHI (R= 0.496) . In addiTo the best of our knowledge, this is the first study to offer evidence that nocturnal sleep breathing parameters exhibit significant amelioration after the mid-term improvement of glycemic control in patients with type 2 diabetes. This favorable change in the sleep breathing data was only observed among good responders, that is to say, subjects who reduced their HbA1c by more than 0.5%. Therefore, our study reinforces the notion that type 2 diabetes exerts a negative impact on sleep breathing that is tightly linked to metabolic control. Remarkably, the most sensitive parameter associated with the enhancement of glycemic control is related to reductions in the AHI. It should be noted that in our study, the group of good responders experienced a 23.3% reduction in their AHI after almost 4 months of metabolic improvement. As OSA significantly elevates the risk of microangiopathy, kidney disease, coronary heart disease and all-cause mortality in patients with type 2 diabetes in comparison with non-diabetic individuals, it seems reasonable to postulate positive clinical consequences for this intervention ,17. In aAlthough 97% of clinicians agreed that OSA is prevalent in subjects with type 2 diabetes, the negative impact that type 2 diabetes exerts on sleep breathing is still under-recognized . TruthfuAlthough intermittent hypoxia and sleep fragmentation, the two hallmarks of OSA, have been associated with insulin resistance and higher rates of type 2 diabetes, the effect of CPAP treatment on insulin resistance and glycemic control is conflicting ,17,23. Tvs. −6.6 events/hour, p = 0.015) [2 were detected in newly diagnosed patients with type 2 diabetes and OSA who were treated for 24 weeks with dapagliflozine, a sodium glucose co-transporter 2 inhibitor, but not in the placebo group [The way in which metabolic control was improved in our study included different antidiabetic drugs, and this condition must be considered when our results are evaluated. In experimental models, the valuable effects of metformin and insulin on sleep breathing have been observed. Thus, in insulin resistant Sprage-Dawley rats, oral treatment with metformin not only prevented, but also reversed apnea episodes . Similar= 0.015) . Howeverbo group . Our stuThe most cost-effective manner of screening sleep breathing abnormalities in type 2 diabetes is a key issue. Appropriate studies to determine whether simple tools such as questionnaires should be included in routine visits to evaluate daytime sleepiness and sleep quality are needed. The administration of the STOP-BANG  questionnaire was able to identify 90.6% of patients with type 2 diabetes and OSA . RecentlThere are certain potential constraints that should be judged in evaluating the results of our study. First, we evaluated a relatively small number of patients with type 2 diabetes with different degrees of OSA, which means that no definite consequences for daily clinical practice can be extrapolated to the general population with type 2 diabetes. Nevertheless, the participants were selected with extreme care to avoid confounding factors associated with sleep breathing such as changes in body weight or body composition. In addition, a control group of non-responders was also considered, as well as a group of subjects without diabetes. Second, we only present evidence about the positive effects of metabolic improvement after a relative short period (4 months). Therefore, larger studies with a longer follow-up are needed to confirm and extend our results, as well as to go deeper into the potential impact of different antidiabetic drugs on nocturnal sleep breathing. Finally, nocturnal sleep breathing was assessed by home sleep testing. Home respiratory polygraphic recordings underscore the AHI, mostly because the total recording time and not the total sleep time is used as the denominator when calculating the AHI. However, home sleep studies have been shown to be a valid alternative to laboratory-based polysomnography . In any In conclusion, an improvement in glycemic control was associated with positive changes in sleep breathing parameters in patients with type 2 diabetes. The main impact was related to significant reductions in the AHI that were independent of weight modifications. Our results confirm the idea that the lung should be considered a target of diabetic complications.