Extensive research has yielded mechanistic insights into how a single cytokine can provoke a disparate range of cellular responses, from proliferation and survival to apoptosis and necrosis. Understanding the intracellular signaling pathways induced by this single cytokine via its two receptors is key to further revelation of its exact functions in the many disease states and immune responses in which it plays a role. In this review, we describe the signaling complexes formed by TNFR1 and TNFR2 that lead to each potential cellular response, namely, canonical and non-canonical NF-κB activation, apoptosis and necrosis. This is followed by a discussion of data from in vivo mouse and human studies to examine the differential impacts of TNFR1 versus TNFR2 signaling.Since its discovery in 1975, TNFα has been a subject of intense study as it plays significant roles in both immunity and cancer. Such attention is well deserved as TNFα is unique in its engagement of pleiotropic signaling  Tumor Necrosis Factor alpha (TNFα) is a central mediator in the immunologic processes of infection control, autoimmunity, allergic disease, as well as the anti-neoplastic activity for which it was named. While too often categorized as simply “pro-inflammatory”, modern research has identified the complex and pleotropic nature of TNFα signaling. However, many gaps in knowledge persist in differentiating the signaling through the two main TNFα receptors (TNFR1 and TNFR2) or how the balance between them may influence downstream consequences. Activation of signaling by TNFα through TNFR1 and TNFR2 initiates a variety of potential outcomes, including cell proliferation, gene activation or cell death. Mediating this variety of cellular responses from just two receptors requires complex control of signal transduction within the cell.The particular response of a given cell to activation by TNFα is determined by receptor expression and intracellular conditions, such as ubiquitination of the signaling complex and the availability of caspases. Herein, we attempt to summarize the difference in intracellular signaling downstream from TNFR1 versus TNFR2 as well as their specific biologic consequences. In addition, we collate the animal model and human clinical studies which independently assess TNFR activity. Overall, we identify that a greater understanding of this pathway may offer opportunities for novel therapeutic targeting as well as treatment optimization for current TNFα inhibition approaches.via TNFR1 is initiated via its DD , that is constitutively expressed on most cell types and is activated by TNFα in either its membrane-bound (mTNFα) or soluble (sTNFα) forms . Followia its DD .In contrast, TNFR2 is limited in both its expression and its activation. Expression of TNFR2 is restricted to particular cell types, including, endothelial cells, fibroblasts and subsets of neurons and immune cells  , 6. AmonFurther adding to the complexity of TNFR signaling is the production of soluble TNFR1 or TNFR2 during cellular activation and the potential for reverse signaling through binding mTNFα. TNFα or other stimuli , lipopolysaccharide (LPS), GM-CSF) induce proteolytic cleavage of TNFRs by the metalloproteinase TNFα converting enzyme  , 11. SolWhen activated by binding TNFα, a core signaling complex is constructed on the cytoplasmic tail of TNFR1. The first step in this process is the trimerization of TNFR1, initiated by contact with TNFα . Once TNThe assembly of TRADD, TRAF2 (or TRAF5), RIPK1, and cIAP1/2 forms the core signaling complex of activated TNFR1. From here, the cellular response mediated by TNFR1 is determined by the ubiquitination of RIPK1 and the availability of caspase molecules , 22. TheThe formation of Complex I is stabilized by linear ubiquitination of RIPK1, which allows the recruitment of additional signaling factors . Additiovia their ubiquitin-binding domains, to activate TGFβ-activated kinase 1 (TAK1) and inhibitor of IκB kinase (IKK). TAK1 is activated by its recruitment with TAK1 and MAP3K7-binding protein (TAB) 2 and TAB3, with TAB2 and TAB3 binding to poly-ubiquitin chains  and p38 pathways , which activate JUN NHpathways , 31. Thepathways , 32. Thuc manner –36. If Croptosis .via Complex IIa or IIb is initiated , pro-caspase 8 (Formation of Complex IIa is initiated when RIPK1 is de-ubiquitinated by cylindromatosis (CYLD). CYLD provides a negative feedback loop for NF-κB activation, as its expression is induced by NF-κB , 41. Wheaspase 8 . The assL, and pro-caspase 8. Thus, Complex IIb includes the same components as Complex IIa, except it lacks TRADD  to activate IKKα, leading to nuclear translocation of the RelB/p52 heterodimer , 33. AltActivation of TNFR2, which lacks the DD that characterizes signaling by TNFR1, most frequently results in cell proliferation and survival. After binding mTNFα, TNFR2 forms a trimer and directly recruits TRAF2 and TRAF1 or TRAF3, albeit with lower affinity than TNFR1-TRADD –57. TRAFvia activation of TNFR1 signaling  is a pathway heavily mediated by TNFR in endo- and epithelial cells. EMT is an essential process for normal tissue repair; epithelial cells take on a migratory mesenchymal phenotype ilaments , 67. Durilaments . Subsequilaments . While bilaments , TNFR2 iilaments . The potilaments , 72 as wilaments –78.Furthermore, the consistent, direct contact between neighboring epithelial cells heightens the potential influence of mTNFα. While genetic deletion of TACE/ADAM17 does not appear to impact bacterial responses in peripheral immune cells , TACE/AD−/− mice have worse outcomes during DSS colitis  were mediated by TNFR2 ; fully humanized ; and variable binding regions fused to a Peg moiety (certolizumab-pegol). Alternatively, etanercept is a dimer of recombinant TNFR binding regions fused to the constant region of a human IgG1 antibody . Althougvia influence over phosphodiesterase (PDE) and cyclic (cAMP)  , furtherc (cAMP) , 72. Of c (cAMP) , 151, tiin vitro  resulting from autosomal dominant mutations in ogenesis . Patientogenesis . Althougogenesis . Multiplogenesis .In 2011, a syndrome including inflammatory skin disease and recurrent infections was linked to autosomal recessive mutations in ADAM17/TACE in two siblings. One sibling died at age 12 of parvovirus B19-associated myocarditis. However, while the other was shown to have exaggerated production of IL-1β and IL-6 in response to lipopolysaccharide (LPS) challenge, he was described as living a “relatively normal life” despite continued recurrent infection . SubsequData from cell cultures, animal models, and humans strongly suggests the balance between TNFR1 and TNFR2 activity has meaningful impacts on health and disease. Unfortunately, mouse models which independently assess TNFR influence are uncommon in the literature and often lack confirmatory validation between research groups. Similarly, clinical studies that independently assess sTNFR levels are typically small and lack tissue-level verification. Clinical utility of anti-TNF treatments should not preclude investigation into differential impacts of TNFRs, given that more targeted blockade could lead to further optimization of clinical benefit, or a reduction in side effects.The current literature on the importance of the TNFRs suggests actionable needs for future research to assess sTNFR1 and sTNFR2 during studies of diseases in which TNFα is known to play a role. Ideally, this research could be bolstered by tissue staining for receptor expression, mTNFα concentration, and/or transcription factor post-translational modifications. Furthermore, functional assessments such as the scratch assay should be considered wherever a role for TNFα-modulation of epithelial or endothelial cellular activity is suspected.However, a notable portion of the differences in downstream signaling through TNFR1 versus TNFR2 is neither transcriptionally regulated nor governed directly by receptor expression. Thus, research into TNFα-modulated diseases using transcript- or proteomics approaches may require direct assessment of the ubiquitination and phosphorylation of signal transducers of the TNFR pathway. Similarly, investigations into disease states or experimental conditions that reveal involvement of pathways that modulate TNFR activity, such as lipid metabolism or neurotransmitter signaling, may be enhanced by directed inquiry into possible TNFR-dependent impacts.PG and IM contributed equally to writing the manuscript and editing the text. IM made the figures and table, with the assistance of PG. All authors contributed to the article and approved the submitted version.This research was supported by the Intramural Research Program of the NIH and NIAID.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Background. Uric acid (UA) renal lithiasis has a high rate of recurrence and a prevalence ranging from 10% and 15%, depending on the population. The most important etiological factor is persistence of urinary pH below 5.5 and one of the most common treatments is alkalization with citrate. Recent studies demonstrated that theobromine, which is abundant in chocolate and cocoa, is a potent inhibitor of UA crystallization. Aim. The aim was to compare the efficacy of citrate versus citrate + theobromine as treatment for UA lithiasis. Methods. This randomized cross-over trial investigated the efficacy of two treatments in 47 patients with UA renal lithiasis. Urine volume, pH, UA excretion, theobromine excretion, and risk of UA crystallization (RUAC) at baseline and at the end of each intervention period were measured. Results. Each treatment significantly reduced the risk of UA crystallization compared to basal values. The RUAC after citrate + theobromine was lower than the RUAC after citrate, although this difference was not statistically significant. Conclusion. The combined consumption of citrate and theobromine may be a promising strategy for the prevention of UA kidney stones. Uric acid (UA) renal lithiasis has a high rate of recurrence ,2, an inWe recently demonstrated that dietary theobromine is a potent inhibitor of UA crystallization in humans ,14. TheoThis paper presents a comparative study of the treatment of UA renal lithiasis with citrate versus citrate + theobromine.This double-blind, randomized, cross-over study recruited 54 volunteer patients at the Urology Service of the Manacor Hospital  who had previous UA renal lithiasis or calcium oxalate monohydrate/UA renal lithiasis.Patients were excluded if they were older than 75 years; had a serum creatinine level above 0.113 mmol/L; had hyperuricemia and/or were taking a diuretic, allopurinol, febuxostat, or other hyperuricemia medication; had an allergy to chocolate or theobromine; were pregnant or lactating; or had an intestinal obstruction. The randomized controlled trials’ registration number is NCT03483532.All subjects received oral and written information about their treatments. Subjects were randomly assigned to citrate group or a citrate + theobromine group for 14 days. Then, after a 7-day washout period, all subjects were switched to the alternate treatment for an additional 14 days . PatientAll patients received two tablets, one at breakfast and the other at dinner. The citrate tablet contained 0.653 mmol K-Cit + 0.933 mmol Mg-Cit. The citrate + theobromine tablet contained 0.653 mmol K-Cit + 0.933 mmol Mg-Cit + 0.333 mmol theobromine extract. Tablets were supplied by Devicare S.L. (Spain). After randomization, there was no blinding of the researchers administering the interventions, but there was blinding of the study participants and the researchers assessing outcomes.Each patient was monitored weekly to ensure the treatment was followed. The dietician also checked for compliance (consumption of at least 80% of pills) at every visit by counting the remaining pills. The basal characteristics of all patients were recorded .Clinical histories were extracted from the electronic medical records. Samples of 24 h urine were collected at baseline to verify satisfaction of the admission criteria and 2 h urine collected after overnight fasting at baseline and after each stage of treatment. Treatment efficacy was evaluated by a test specially designed to measure the ability of urine to inhibit the crystallization of UA  test)  and urinUrine volume, pH, creatinine, UA, and RUAC test results were determined for each sample. Urinary pH was measured using a Crison pH-meter GLP22, creatinine with the kinetic Jaffe method, and UA was measured using the uricase method.The RUAC test was carried out in polystyrene non-treated well plates . First, 5 mL of each urine sample was added to each of the 6 wells. The first well had no additions. Hydrochloric acid and/or UA were added to the other wells to promote the crystallization of UA A. The 6 Type 2 diabetes was diagnosed if subjects presented with fasting serum glucose of at least 7.0 mmol/L and/or glycated hemoglobin of at least 6.5% . Blood pt-test or Wilcoxon’s signed-rank paired test for continuous parameters and McNemar test for categorical parameters. Inter-group comparisons after the intervention were assessed using analysis of covariance with adjustment for changes in continuous parameters according to baseline values. A two-tailed p-value less than 0.05 was considered statistically significant. Statistical analyses were performed using SPSS version 23.0 .Data are presented as means ± standard deviations or numbers (percentages). Intra-group differences before (T0) vs. after (T1) the intervention were evaluated using a paired-samples The study design was approved by the Research Committee of Hospital Manacor and Research Ethics Committee of Balearic Islands (CEI-IB) (IB3414). All patients provided written informed consent before participation.Forty-seven patients  completed both treatments in this cross-over clinical study . The meap < 0.01 and p < 0.001, respectively).p < 0.001). No patients had to discontinue participation in the study due to adverse events.As expected, the urine of patients who received citrate + theobromine had a significantly higher concentration of theobromine than patients at baseline and patients who received citrate alone (Considering the solubility of UA in aqueous media, urine with a normal UA content only leads to UA lithiasis when the pH is below 5.5 . Thus, cOur results showed that treatment with citrate or citrate + theobromine significantly reduced the risk of UA lithiasis relative to baseline . AlthougThe exclusive use of theobromine could be considered for the treatment of patients with UA lithiasis. However, it is interesting to take into account that the combined use of citrate and theobromine has a synergistic effect, because small increases in urinary pH greatly enhance the effects of theobromine as an inhibitor of UA crystallization  and reduThis is the first study of patients with UA lithiasis to evaluate the effects of a combination of citrate and theobromine. A limitation is that we only examined a small number of patients from a single center. A study with a larger and more diverse sample is necessary for confirmation.The combined use of citrate and theobromine may be an effective strategy to prevent the formation of UA kidney stones. The inhibitory effect of theobromine on UA crystallization allows use of lower doses of citrate and thereby prevents the generation of high urinary pH that could induce the formation of insoluble calcium phosphates. The combined treatment also provides protection against UA crystallization if there is an excessive drop in urinary pH.


The SNX-PXA-RGS-PXC subfamily of sorting nexins (SNXs) belongs to the superfamily of SNX proteins. SNXs are characterized by the presence of a common phox-homology (PX) domain, along with other functional domains that play versatile roles in cellular signaling and membrane trafficking. In addition to the PX domain, the SNX-PXA-RGS-PXC subfamily, except for SNX19, contains a unique RGS  domain that serves as GTPase activating proteins (GAPs), which accelerates GTP hydrolysis on the G protein α subunit, resulting in termination of G protein-coupled receptor (GPCR) signaling. Moreover, the PX domain selectively interacts with phosphatidylinositol-3-phosphate and other phosphoinositides found in endosomal membranes, while also associating with various intracellular proteins. Although SNX19 lacks an RGS domain, all members of the SNX-PXA-RGS-PXC subfamily serve as dual regulators of receptor cargo signaling and endosomal trafficking. This review discusses the known and proposed functions of the SNX-PXA-RGS-PXC subfamily and how it participates in receptor signaling (both GPCR and non-GPCR) and endosomal-based membrane trafficking. Furthermore, we discuss the difference of this subfamily of SNXs from other subfamilies, such as SNX-BAR nexins (Bin-Amphiphysin-Rvs) that are associated with retromer or other retrieval complexes for the regulation of receptor signaling and membrane trafficking. Emerging evidence has shown that the dysregulation and malfunction of this subfamily of sorting nexins lead to various pathophysiological processes and disorders, including hypertension. Receptor-mediated signaling and membrane trafficking processes are intimately interconnected with the endosomes . Internaphox and p47phox, actively engages in protein–lipid and protein–protein interactions [The SNX family has a phox homology (PX) domain, capable of phosphoinositide binding, which enables SNX targeting to endosomal membranes by binding to phosphatidylinositols, most commonly phosphatidylinositol 3-phosphate (PI(3)P) ,6. SNXs ractions ,6. To daractions ,6,7,8. BThe SNX-PXA-RGS-PXC subfamily is comprised of SNX13 , SNX14, SNX19, and SNX25. This subfamily of SNXs contains two N-terminal helical transmembrane domains, followed by a PX-associated domain (PXA), a regulators of G protein signaling (RGS) domain, the PX domain, and a C-terminal PX-associated (PXC) domain ,8. Integrated transmembrane domains (IMDs), which are two, close short hydrophobic sequences, are involved in membrane tethering ,6. RGS d1R [The PX domain of the SNX-PXA-RGS-PXC subfamily is similar to the PX domains of all other SNX subfamilies, with around 100-130 residues, comprised of three β-strands and three α-helices . The con1R . HoweverThe RGS domain is present in SNX13, SNX14, and SNX25, but not SNX19  Table 3Table 3. 1R may interact because SNX13 105820C and DRD1 G-94 have been associated with an increase in albumin excretion in a twin pair study [1R signaling.Similar to the canonical RGS proteins , the RGSir study . Therefo6R) [6R signaling by sequestering Gαs.The RGS domain does not have to function as a GAP to regulate GPCR signaling in all cases. For example, the RGS domain of SNX14 does not have GAP activity, but specifically binds to and sequesters Gαs, inhibiting the downstream cAMP production caused by the activation of serotonin receptor 6 (5-HT6R) . The bin6R) . This su1R, cAMP production, and promotion of effective D1R signaling [As discussed above, the RGS domain facilitates the SNX-PXA-RGS-PXC subfamily in the regulation of GPCR signaling by sequestering Gαs with  or withoignaling . SNX19 aignaling .2 to PIP3 and suppresses the phosphorylation of Akt/protein kinase B (PKB), playing critical roles in insulin receptor signaling [In addition to GPCRs, the SNX-PXA-RGS-PXC subfamily also regulates the signaling of non-GPCRs. In mouse insulinoma cells exposed to high glucose concentration, SNX19 inhibits the conversion of PIPignaling . In NIH3ignaling . Of noteignaling ,23. Deleignaling .Upon endocytosis, receptors (GPCR or non-GPCR) are trafficked to early endosomes, and then sorted to distinct destinations: lysosomal-mediated degradation or recycling to the plasma membrane or other organelle compartments for reuse . As discEndolysosomal trafficking is the major pathway by which transmembrane receptors are downregulated. Membrane contact sites (MCS) between lysosomes and endosomes, as well as mitochondria and endoplasmic reticulum (ER), are regions of phospholipid exchange, which regulate the sorting of receptors at late endosomes for degradation ,41. In ySNX13 binds to a wide range of phosphoinositides  and playSnx13-null mice [SNX13.Morphological evidence also demonstrated the critical role of SNX13 in lysosomal degradation. Two distinct endosome morphologies, vesicular and tubular, are involved in receptor degradation and recycling pathways, respectively . An unusull mice . This in2 [SNX14 causes accumulation of aberrant cytoplasmic vacuoles, suggesting defects in endolysosomal homeostasis [6R, facilitating its endolysosomal degradation [The SNX14 PX domain preferentially binds to PIP2 , a key c2 ,10, impl2 . Similar2 , SNX14 teostasis . SNX14 aradation . In yeasradation .Snx19 decreases the transmembrane protein, insulinoma-associated protein 2 (IA-2), and the number of dense core vesicles (DCV) in MIN6 cells, a mouse pancreatic β-cell line. The decrease in the IA-2 protein expression and the amount of DCV correlate with the increase in autophagic lysosomal activity [Knockdown of activity , which iactivity .SNX25 interacts with tropomyosin receptor kinase B (TrkB) in early endosomes, late endosomes, and lysosomes in hippocampal neurons and HEK293T cells . SNX25 o1R plasma membrane recycling [1R at the plasma membrane, specifically in lipid rafts. This colocalization is increased by treatment with fenoldopam, a D1-like receptor agonist [SNX19 by its specific siRNA decreases D1R lipid raft localization, plasma membrane expression, and signaling [1R recycling, probably via palmitoylation and lipid raft targeting.Besides mediating endolysosomal degradation, as described above , the SNXecycling . In rena agonist . The inc agonist . Depletiignaling . All of 1R and D2R in HEK293 cells, and overexpression of SNX25 perturbs the endocytosis of D1R and D2R and recycling of the D2R. Moreover, knockdown of SNX25 causes a subsequent decrease in D2R plasma membrane expression, suggesting that SNX25 plays a role in D2R membrane recycling [SNX25 interacts with Decycling .5R signaling [1R [SNX-BAR, another subfamily of SNXs, is known to regulate receptor signaling and orchestrate membrane trafficking through distinct mechanisms. Although there are few overlaps with the SNX-PXA-RGS-PXC subfamily, the SNX-BAR sorting nexin subfamily regulates different types of receptor cargoes. For example, SNX1 is important for Dignaling , while tling [1R , insulinling [1R , and insling [1R  in renalling [1R ,55, cellling [1R , TGN38 [ling [1R , vacuolaling [1R , β-site ling [1R , PIN1 [6ling [1R , and PINling [1R . SNX4 reling [1R , BACE1 [ling [1R , and E-cling [1R . SNX18 rling [1R .Distinct from the SNX-PXA-RGS-PXC subfamily, the SNX-BAR subfamily shares a close relationship with retromers and other retrieval machineries. SNX-BAR subfamily contains a dimeric Bin-Amphiphysin-Rvs (BAR) domain with a positively charged curved surface that binds to membranes . The BAR1R signaling is regulated by SNX5, a member of SNX-BAR without the RGS domain. Both SNX5 and SNX19 regulate D1R internalization in early endosomes [1R subsequent trafficking and lysosomal degradation. SNX5 and SNX19 differently regulate D1R recycling  plays some roles similar to RGS proteins. Canonical RGS proteins regulate the signaling of their GPCR cargo, by binding directly to Gαs, and function as a GAP . SNX13, ndosomes ,51. It iecycling .1R signaling, probably through G protein-coupled receptor kinase (GRK) 4-mediated phosphorylation and desensitization of D1R, but not by targeting D1R to lipid rafts [1R-stimulated cAMP production [1R palmitoylation and targeting into lipid rafts, where adenylate cyclase 6 is located [1R signaling [1R signaling and internalization and if they regulate the degradation of D1R in lysosomes remains to be determined.SNX5 regulates Did rafts . As prevoduction . Therefo located , to reguignaling . How SNXCaenorhabditis elegans coelomocyte [1R is regulated by ubiquitination [1R signaling and trafficking. Therefore, it is possible that ubiquitin-tagged or palmitoylated D1R is sequestered by different ESCRT-subunits, using distinct mechanisms for its lysosomal degradation [In contrast to the SNX-BAR subfamily, the SNX-PXA-RGS-PXC subfamily has a different preference for trafficking routes for its receptor cargoes. Based on recent limited studies, the SNX-PXA-RGS-PXC subfamily mainly transports receptor cargoes, via the endolysosomal pathway for degradation ,42,43,45lomocyte ,77. Whetlomocyte ,78. Ubiqlomocyte ,80 and plomocyte ,82 are itination  and palmtination , and as tination  and SNX1tination  regulateradation .2AR, to regulate their recycling [The SNX-PXA-RGS-PXC subfamily has differences from the other SNX subfamilies in its role in receptor signaling and trafficking. For example, SNX3, a member of the SNX-PX subfamily, interacts with the retromer complex to regulate cargoes, such as the divalent metal transporter 1-II (DMT1-II) recycling from the endosome to TGN . SNX17, ecycling .As aforementioned, the SNX-PXA-RGS-PXC subfamily regulates the signaling and trafficking of internalized cargoes, including GPCRs and non-GPCRs, mainly leading them to endolysosomal degradation ,13,42. TSnx13 in mice is embryonically lethal, indicating that SNX13-regulated endocytosis dynamics is essential in mouse development [SNX13 forms a heterotrimeric complex with Gαs and Hrs in endosomes, critical in targeting ubiquitinated membrane cargoes, such as EGFR, for sequestration into multivesicular bodies and subsequent degradation in lysosomes ,42. Germelopment . SNX13 pelopment . SNX13 ielopment ,99, indi6R [SNX14 is important in normal neuronal excitability and synaptic transmission . SNX14, 6R  and prob6R ,91,100, 6R .1R and Golgi-associated DHHC-type zinc finger [1R palmitoylation, trafficking from anterograde trafficking, and recycling [1R in the lipid rafts [1R signaling complex components are localized, including GRK4, G proteins, adenylyl cyclases, and effector proteins, such as NADPH oxidase, Na+-K+-ATPase, and Na+-H+ exchanger (NHE) 3, for appropriate cellular responses and functions [1R targeting to lipid rafts because the deletion of the PX domain results in the D1R mistargeting to non-lipid rafts [SNX19 knockdown not only decreases the D1R-induced increase in cAMP production, but also abrogates the ability of the D1R to inhibit renal tubular sodium reabsorption [Snx19 knockdown increases the systolic blood pressure of C57BL/6J mice [SNX19, rs2298566, increases the risk of coronary heart disease [SNX19 interacts with Dc finger , a palmic finger  and, as ecycling . This prid rafts , where ounctions ,105,106.id rafts . Moreovesorption . Importa/6J mice , indicat/6J mice , a major/6J mice . SNX19 m/6J mice . A singl disease .SNX25 is a potential candidate gene for distal hereditary motor neuropathies [SNX25 is involved in the lysosomal degradation of the TGF-β receptor  and the opathies  and a geopathies .1R signaling through palmitoylation. Further studies are needed to determine the precise molecular mechanisms by which SNX19 regulates palmitoylation in the Golgi and the plasma membrane.Emerging evidence has demonstrated that the SNX-PXA-RGS-PXC subfamily and their interacting partners are critical regulators for receptor signaling and membrane trafficking. The receptor cargoes can be GPCRs and non-GPCRs through which cells respond to both extracellular and intracellular stimulation. The complex interaction between cellular signaling and endosomal-based membrane trafficking plays an essential role in maintaining cellular homeostasis and versatile functions. SNX13, 14, and 25 have a unique RGS domain, which presumably serves as GAP, attenuating signals associated with GPCR. It is important to examine the molecular mechanisms of GAP both in vitro and in vivo for all three SNXs of the above subfamily. Current evidence suggests that SNX 19 lacks an RGS domain, indicating that it is unable to serve as a GAP. However, SNX19 has emerged to regulate GPCR in other ways, for example, facilitating DDifferent from retromer-dependent SNXs, which retrieve their cargoes through recycling to plasma membrane, TGN or other organelles in retromer-dependent and -independent mechanisms, the SNX-PXA-RGS-PXC subfamily mainly regulates their cargo receptors for endolysosomal degradation. The SNX-PXA-RGS-PXC subfamily regulates receptor recycling for certain cargoes as well, but the molecular switch that controls the different post-endocytic trafficking routes remains to be identified.1R and renal sodium transporters to different cell surface domains. We need to study how such processes can control polarized apical and basolateral locations and cellular function for sodium transport in the renal proximal tubule and other nephron segments. It is expected that the SNX-PXA-RGS-PXC subfamily, as with other SNXs, plays diverse roles on the regulation of the intricately linked signaling and trafficking for precise cellular functional outputs. Studies in appropriate conditional or non-conditional global knockout and transgenic or gene rescue animal models will advance our understanding of the physiological functions in vivo of the SNX-PXA-RGS-PXC subfamily and their associated pathophysiological disorders, which could lead to potential novel therapies targeting this SNX subfamily.While cellular signaling directs the distinct receptor cargo trafficking routes, cargo trafficking actively shapes the cellular signaling response as well, by altering the location and time of specific signaling events. The incomplete understanding of the role that RGS-PXC SNX plays in cell polarity warrants further research. For example, it is important to understand the exact function of the SNX-PXA-RGS-PXC subfamily in the sorting of D


Dear Editor,1.Human T-cell Leukemia Virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL). Although the majority of HTLV-1-infected individuals remain asymptomatic, in endemic regions such as Southern Japan, the Caribbean, some parts of Oceania, Romania, Central and South America, Northern Iran, and Central Africa, up to 4% of people living with HTLV-1 develop ATL. Although combination therapy with IFN-α and AZT as a first-line treatment prolongs survival of patients with ATL significantly, prognosis for patients with aggressive forms of ATL is poor due to intrinsic chemoresistance and relapse2. Tax drives the ATL epigenetic signature through the NF-κB pathway and inactivates the tumor-suppressor protein p535. Inhibition of exportin-1 (CRM1/XPO1), the key nuclear export factor for proteins containing the typical leucine-rich nuclear export signal (NES), has been shown to inhibit NF-κB activity and induce p53-signaling pathways6, whereas XPO1 inhibitors display efficacy against different types of cancer9. Recently, the first-in-class XPO1 inhibitor selinexor (XPOVIO®) has been approved by the US Food and Drug Administration for the treatment of relapsed and refractory multiple myeloma and for relapsed diffuse large B-cell lymphoma. Selinexor is a highly selective and covalent inhibitor of XPO1 preventing export of cargo proteins to the cytoplasm, resulting in nuclear accumulation of cargo proteins12. Here, we investigate the therapeutic potential of selinexor in ATL by combining a two-stage targeted and systems analysis of ex vivo ATL transcriptomes with functional validation HTLV-1-transformed CD4+ cells.The viral proteins Tax and HBZ play a major role in HTLV-1-induced carcinogenesis+CD25+CADM1+, we first investigated the possible relationship of XPO1 to these three signature genes, as well to p53 and NFκB signaling, which are the major regulators of apoptosis and survival in ATL15. As shown in Fig. hi phenotype as compared to healthy controls, which was significantly and positively correlated to ATL leukemic markers CD4, CD25/IL2RA and CADM1/TSCL1 in two independent patient cohorts from different HTLV-1 endemic areas . In contrast, a strong negative correlation between XPO1 and IL2RA was observed in PBMCs from healthy controls in the Brazilian cohort . This suggests a pathobiological role for XPO1 in ATL leukemogenesis. Likewise, increased XPO1 transcript levels were found to be associated with clinical progression to aggressive ATL  or Hbz-low expressing (<10 TPM) ATL patients, nor was there any difference in XPO1 expression between Tax-positive and Tax-negative ATL patient samples . In agreement with this finding, we observed a significant positive correlation between XPO1 and CD4 transcript levels  and a negative correlation for CD8B transcripts (a proxy for antileukemic CD8+ cells) in the Japanese cohort, which we confirmed by flow cytometry in the Brazilian cohort  and several proapoptotic caspases . As a negative control, we found that inflammatory caspases CASP1, CASP4, and CASP5 were not correlated to the XPO1 gene module . XPO1 transcript levels were also not correlated to gender (not shown), age, or patient survival  and CASP7  with age at ATL diagnosis, suggesting that apoptosis might be protective in vivo by leading to later disease onset. In addition, “executor” caspase CASP7  was positively correlated to ex vivo apoptosis, measured by short-term culture of unstimulated patient PBMCs. In agreement with a protective role for apoptosis in ATL, CASP10 levels showed a trend of correlation to longer survival , which remains to be investigated in larger cohorts. Unfortunately, no functional assay or survival data were available for the larger Japanese cohort.Since ATL leukemic cells are characterized as CD4ort Fig. , which wATL Fig. . Noteworort Fig. . Hintingval Fig. , arguingXPO1 expression is strongly correlated to NFKB1 and TP53 transcript levels  to elucidate the effect of XPO1 inhibition by selinexor  upon p53 signaling and downstream apoptosis. As shown in Fig. CASP3, CASP7, and CASP10 in ATL patients, we found that a pan-caspase inhibitor Q-VD-OPh (targeting caspases 3-7-8-9-10-12) was able to completely block PARP cleavage and caspase-3 activation , which has been identified as a sensitive predictor of IFN + AZT therapy failure20. Therefore, IRF4-overexpressing patients21 likely to fail first-line therapy might preferentially benefit from XPO1 targeting.Of note, the ®) currently already available for the treatment of multiple myeloma and DLBCL and under investigation in multiple clinical trials for hematological and solid malignancies, these data provide a strong rationale for further therapeutic evaluation of selinexor to improve the outcome of patients with ATL.In conclusion, this study demonstrates that pharmacological inhibition of XPO1 by selinexor is a potential novel therapeutic strategy in ATL, by triggering the proapoptotic p53 pathway leading to caspase-dependent apoptosis. With selinexor (XPOVIOSupplemental Figures


Major depressive disorder (MDD) is a serious mental disease with negative effects on both mental and physical health of the patient. Currently, antidepressants are among the major ways to ease or treat MDD. However, the existing antidepressants have limited efficacy in treating MDD, with a large fraction of patients either responding inadequately or differently to antidepressants during the treatment. Pharmacogenetics studies have found that the genetic features of some genes are associated with the antidepressant efficacy. In order to obtain a better understanding on the relationship between the genetic factors and antidepressant treatment response, we compiled a list of 233 single-nucleotide polymorphisms (SNPs) significantly associated with the antidepressant efficacy in treating MDD. Of the 13 non-synonymous SNPs in the list, three  may influence the structures and function of the corresponding proteins. Besides, the influence of rs1065852 on the structure of CYP2D6 was further investigated via molecular dynamics simulations. Our results showed that compared to the native CYP2D6 the flexibility of the F-G loop was reduced in the mutant. As a portion of the substrate access channel, the lower flexibility of F-G loop may reduce the ability of the substrates to enter the channel, which may be the reason for the lower enzyme activity of mutant. This study may help us to understand the impact of genetic variation on antidepressant efficacy and provide clues for developing new antidepressants. Major depressive disorder (MDD) is a serious mental disorder that influences ~6% population worldwide , 2. The Currently, antidepressants are among the major ways to treat or alleviate MDD. The available antidepressants can be classified into several types according to their structure and the way they work, including selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, and the other antidepressants. However, studies have shown that the existing antidepressants have limited efficacy in treating MDD, and the response of patients to antidepressants is difficult to predict . For exaCYP2D6, CYP1A2, CYP3A4, and CYP2C19, have been found to play important roles in the metabolism of antidepressants  and 5-hydroxytryptamine receptor 2A (HTR2A), genotypes are also associated with the antidepressant efficacy  is significantly associated with response to antidepressants in MDD (HTR1B), HTR1A, and HTR2A are significantly associated with efficacy of antidepressants (*D) study (*D study identified an SNP (rs2456568) on hypoxanthine phosphoribosyltransferase pseudogene 4 (HPRTP4) at the genome-wide significance level (AUTS2) were found to be related to antidepressant response  study , the GenD) study , and theD) study . AlthougD) study , a meta-ce level . In anotresponse .Although a number of SNPs have been found to be significantly associated with antidepressant efficacy in treating MDD, it is still unclear how these SNPs affect the interaction between proteins and the drugs, as well as the response of antidepressants. Hence, exploring the correlation between the SNPs and the structures of the corresponding proteins may provide valuable information to understand the molecular mechanism underlying response to antidepressants and help us to develop novel antidepressants. In this article, we implemented a comprehensive curation of SNPs related with antidepressant efficacy from genetic studies and identified the non-synonymous SNPs (nsSNPs) potentially influencing the biological function and structure of the proteins.https://www.pharmgkb.org/), a comprehensive resource for clinical information, gene-drug associations, and genotype-phenotype relationships (https://www.ncbi.nlm.nih.gov/pubmed/) via the query term “ AND (Antidepressive Agents [Mesh]) AND .” For these publications, the redundant ones were removed. Then, the abstracts of the remaining publications were reviewed, and only studies related to antidepressant response were selected. Most of these studies were GWASs, meta-analysis, and candidate gene analysis of antidepressant responses. In each case, we selected only the SNPs that were significantly associated with the response of antidepressants in MDD. To reduce false-positive findings, the publications reporting negative or insignificant correlations were excluded, although some SNPs explored in these studies might be really associated with antidepressant responses. The full texts of the selected publications were examined to ensure the conclusions were consistent with the content. We narrowed our selection by focusing on those purporting one or more SNPs significantly associated with antidepressant responses. Finally, we retrieved 117 publications , PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/), and SNAP2 (https://rostlab.org/services/snap2web/). SIFT is a tool to predict the change of protein function caused by single amino acid mutation based on homologous protein sequence and the physical properties of amino acids . I-MUTANT can detect the changes of protein stability according to single amino acid substitution  was utilized to evaluate the evolutionary conservation of amino acid positions in protein based on the phylogenetic relationships between homologous protein sequences . Then, the structure of mutant protein was constructed based on the structure of native protein by SWISS-MODEL (https://swissmodel.expasy.org)  simulation for the native and mutant proteins, respectively. We selected the most closely related protein structure from PDB  . Finallyasy.org) .N, constant number; V, volume; and T, temperature) ensemble was first conducted for 1.0 ns and stabilized the temperature of the system at 300 K; then, an NPT  ensemble was conducted for 5.0 ns to ensure the system was well-equilibrated with respect to pressure and density. After the system is well-equilibrated at the expected temperature and pressure, we performed the MD simulations for 200 ns to explore the structural deviation and fluctuation of native and mutant protein due to deleterious nsSNPs. Finally, in order to evaluate the convergence of the MD simulations, we calculated the root-mean-square deviation (RMSD). Furthermore, root-mean-square fluctuation (RMSF) was calculated to assess the differences in structural flexibility between the native and mutant proteins. The RMSD and RMSF were obtained from the trajectory files of the MD results, which were produced after the MD simulation.We used the AMBER99SB-ILDN force field in both native and mutant model systems . The proHTR1A, HTR1B, HTR2A, and HTR7; one dopamine receptor, that is, DRD3; two corticotropin-releasing hormone receptors, that is, CRHR1 and CRHR2; two glutamate receptors, that is, GRIK2 and GRIK4; two serotonin biosynthesis genes, that is, TPH1 and TPH2; and some genes encoding transporters, that is, SLC6A1, SLC6A2, SLC6A3, SLC6A4, SLC39A14, and ABCA1. In addition, some genes were related to drug transport, that is, CACNA1A, DTNBP1, GDNF, CRH, SLC6A2, SLC6A3, GAL, SNCA, and CNR1; some genes were involved in the exogenous drug catabolic process, that is, CYP1A2, CYP2C19, and CYP2D6; and some genes were related to response to drug . The functional diversity of these genes clearly indicated the complexity of the mechanisms for antidepressant response. In addition, ABCB1, TPH2, ANO2, ZNF385D, and CYP1A2 appeared more frequently in these genes. For these SNPs, most were located in the non-coding regions. Currently, it still remains a significant challenge to explain how SNPs located in intronic or intergenic regions affect drug response. In addition, because synonymous SNPs in the coding region do not change the protein sequence, it is difficult to experimentally address the function of every mutation seen in these regions. Therefore, we focused only on the nsSNPs in the coding region in the following analyses  into a serine (S) occurred at position 34 due to deleterious nsSNPs rs1065852 . The difThe native structure of CYP2D6 was obtained from PDB (PDB ID: 3QM4) . Then, wWe analyzed the RMSDs for backbone of the native and mutant CYP2D6 to evaluate the convergence of the systems. Root-mean-square deviation indicates the average change in displacement of the selected atoms for a particular frame in respect of a reference coordinate system. The initial structures were used as the references of RMSDs. For purpose of detecting the changes of flexibility between the native and mutant CYP2D6 structures, we calculated the RMSFs. The results are shown in Although a number of SNPs are found to be significantly associated with the response of antidepressants in MDD, it is still unclear how they affect the interaction between genes carrying these SNPs and antidepressants. In this study, we collected the SNPs significantly associated with the response of antidepressants and explored the potential mechanism underlying the different antidepressant efficacy among MDD patients. Most of the SNPs were included in the intronic or intergenic regions. For the 13 nsSNPs, three of them  were predicted to be deleterious to the corresponding proteins. Evolutionary conservation analysis showed that P34S (rs1065852) was the only one located in the conserved protein domain, indicating it may be important for maintaining protein function. Subsequently, the results of the MD simulations revealed that the flexibility of the F-G loop for mutant was reduced compared to the native CYP2D6. As a constituent portion of the substrate access channel, this may affect the substrates that enter into the channel entrance. Hence, this may be the reason for the low enzyme activity of mutant.*4,CYP2D6*5, and CYP2D6*10) may be predicting patient treatment outcomes. In our study, we obtained the results of Han et al. , which is a tool that analyzes the structural effects of a point mutation in protein sequence (in vivo (The results of the MD simulations indicated that the flexibility of the F-G loop for mutant was reduced compared to the native CYP2D6. The P34Srs1065852) substitution is located in a highly conserved region encoding the proline-rich N-terminus in the three-dimensional structure of CYP2D6 , which wsequence . For amisequence . And thesequence , which msequence . Therefosequence , 64. The852 subst(in vivo . The res(in vivo . Kim et (in vivo  indicateGABRQ), whose genotype AA + AT (F) is significantly associated with increased response to venlafaxine in people with MDD as compared to genotype TT(I) (KMT2E), whose genotype GG(G) is significantly associated with increased response to duloxetine in people with MDD as compared to genotype GT(C)  is located in the coding region of γ-aminobutyric acid type A receptor, subunit theta (pe TT(I) . GABRQ ipe TT(I) . The mutpe TT(I) . The SNPpe GT(C) . The oripe GT(C) .HTR2A carrying rs6314 is related to postsynaptic serotonin signaling and is a target for many antidepressants (HTR2A gene and leads to the change between histidine (His) and tyrosine (Tyr) at position 452. In addition, rs6311, rs17288723, rs7997012, rs9316233, rs6313, and rs2770296 of this gene are also significantly associated with antidepressant efficacy in MDD. This may result in the changes in protein structure and affect the interaction between HTR2A and antidepressants. In addition, several earlier studies found that rs6265 genotypes in BDNF were significantly associated with the response to antidepressants in MDD  were likely to be deleterious in the encoding proteins, particularly P34S (rs1065852) in CYP2D6. Results of the subsequent MD simulation regarding rs1065852 indicated that the flexibility of the F-G loop for mutant was reduced compared to the native CYP2D6, which may be responsible for the decrease in enzyme activity by hindering the substrate recognition and access. In addition, our results may provide theoretical basis for the development of new antidepressants and personalized medicine in MDD.All datasets generated for this study are included in the article/JX, MY, YP, and JW: conceived, designed, and performed the experiments and wrote the paper. JX, MY, and YP: analyzed the data.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In many Western countries, the total fertility rate (TFR) of immigrant women has declined over the last decades. This paper proposes two methods for investigating such changes in the aggregate immigrant fertility level: what-if scenarios and a formal decomposition. Both methods disentangle the effect of changed composition—by origin area and duration of stay—from the effect of changed fertility within subgroups. The methods are applied to data from Norway, where immigrant TFR declined from 2.6 births per women in 2000 to below 2.0 in 2017. The results show that this decline is not due to successful integration, nor changed composition of immigrant women by origin area or duration of stay. A main reason for the decline is found among newly arrived immigrant women, particularly from Asia. They have a considerably lower fertility now than what the newly arrived had 15–20 years ago. After investigating several possible reasons for the TFR decline among the newly arrived, decreased fertility in origin areas is suggested as a key driver.The online version of this article (10.1007/s10680-019-09541-0) contains supplementary material, which is available to authorized users. The total fertility rate (TFR) of immigrant women has declined in many Western countries, as shown in Fig. Immigrants’ fertility has received attention in many Western countries, for several reasons. Many immigrant women are in their childbearing ages; hence, their fertility has large impact on the number of births. In Western Europe in 2017, where 13% of the population was foreign-born, every fourth birth was to a foreign-born mother Eurostat , b. HencNumerous studies have contributed to explaining immigrant’s fertility behaviour, displaying how fertility patterns vary between different groups of immigrant women, for instance by origin area or duration of stay. However, not much attention has been devoted to understanding changes in the aggregate fertility level of immigrants in a country.proportion of women with long duration of stay increases. Another factor that could change immigrant’s TFR is changed composition of immigrant women by origin area, for instance if the proportion of immigrants from low-fertility countries increases. Yet another possible reason could be changed fertility within subgroups of immigrant women (by duration of stay and country of origin).The total fertility rate is the most common aggregate measure of fertility, summarizing current fertility patterns into a single number. Figures on immigrant TFR are regularly published in many countries and used by policy makers and others in the public debate. However, there is a risk of drawing too quick conclusions based on this summary measure. For instance, a decreased immigrant TFR may be interpreted as a sign of successful integration of immigrants. However, even if integration often implies that an immigrant woman’s fertility decreases by her duration of stay, this will only lead to decreased TFR for all immigrant women if the Understanding the determinants of a changed immigrant TFR is essential in order to implement appropriate policy responses and better forecast future fertility. Therefore, the aim of this paper is to show how changes in the overall immigrant TFR can be scrutinized.The paper is organized as follows: The first part briefly reviews how previous research on migrant fertility has identified two factors as particularly important for immigrant women’s fertility: area of origin and duration of stay in the destination country.what-if-scenarios and a formal decomposition. These methods have not, to my knowledge, previously been used to investigate immigrant fertility trends. The methods are applied to data from Norway, where TFR among immigrant women decreased from 2.6 births per woman in 2000 to less than 2.0 in 2017.Secondly, two approaches are introduced for disentangling the TFR effect of changed composition by origin area and duration of stay from the effect of changed fertility behaviour within subgroups of immigrant women (by origin area and duration of stay): within subgroups (by origin area and duration of stay). Almost half the decrease is due to the newly arrived immigrant women having a noticeable lower fertility now than the newly arrived had in 2000.The two approaches broadly give the same conclusion: Although immigrants’ fertility often declines with their duration of stay, this does not explain why the immigrant TFR in Norway has fallen since 2000, nor does changed composition by origin area. The decrease in immigrant TFR in this period is mainly due to changed fertility Furthermore, this TFR decrease among the newly arrived immigrant women is decomposed by reason for immigration. The results show that a large part of their decline is linked to the family migrants—women who migrate for family-(re)unification. Their share among all newly arrived immigrants has decreased since 2000, and so has their fertility. Among the newly arrived family immigrants from Asia, TFR declined by more than two births per women.This TFR decrease among newly arrived family migrants, particularly from Asia, is investigated by exploring other factors such as age at arrival, education, births before migration and whether the male partner was a migrant. The TFR trends of newly arrived family immigrants are also compared with TFR trends in their countries of origin. This latter approach suggests that the fertility decline among newly arrived family migrants from Non-Western countries may, at least partly, reflect a declined fertility in the country of origin. Thus, if fertility continues to decline in high-fertility countries, as the United Nations assumes, the results of this paper suggest that further fertility declines may be expected among newly arrived immigrants from these countries in Western societies.Although the TFR of immigrants is widely produced and used, previous research has not focused much on explaining changes over time in this macro-measure. However, on a more micro-level, substantial work has been done to uncover factors that can explain fertility patterns among different groups of immigrant women in Western countries.1duration of stay. The hypothesis of interrelated events (or family formation hypothesis) emphasizes that many immigrant women migrate because they are starting a family, so fertility will be particularly high right after migration. The adaptation hypothesis points out that a person’s fertility behaviour is affected by her current context, so when an immigrant settles in a new country, she will adapt over time to this country’s fertility norms. The disruption hypothesis, on the other hand, argues that migration may be stressful and often involves separations of spouses and depressed income, so we can expect a temporary drop in fertility around the time of migration.From this research, two factors appear particularly crucial for an immigrant woman’s fertility: her origin area and her duration of stay. These two factors will play a key role in the methods presented later in this paper. Several hypotheses may explain their importance. A thorough overview of migrant fertility hypotheses are presented in, for instance, Kulu , Kulu anAll these three hypotheses imply that subgroups with different durations of stay have different fertility norms. Hence, a changing composition of immigrant women by duration of stay would also change the general immigrant TFR.origin area. According to the socialization hypothesis, people are formed by their childhood experiences, so that even if they move to a new country, their fertility is defined by the norms and behaviours they once were socialized into. As a complement to this, the selection hypothesis states that immigrants may be a select group compared to nonmigrants in their origin area. Immigrant women’s reason for migration may reveal some of this selection. For instance, women who migrate for work may have lower fertility preferences than an average woman from the same origin area.The second group of hypotheses are concerned with the role of immigrants’ When subgroups of immigrant women from different origin areas have different fertility norms, a changing composition of immigrant women by origin area would also change the overall immigrant TFR. Also, if subgroups of immigrant women with different reasons for migration have different fertility norms, a changing composition of immigrant women by reason for migration can affect the TFR for all immigrants.The significance of duration of stay and origin area is dominant in the literature on migrant fertility. In addition, migrant fertility research has also identified other factors that may affect an immigrant woman’s fertility, such as age at migration, education, residential segregation, whether the male partner is also a migrant and her number of births before migration. Factors like these may explain why we sometimes see changed fertility within subgroups of immigrant women by origin and duration of stay.share of immigrant women with long duration of stay increases. The aim of this paper is to use the factors presented above to identify subgroups of immigrant women whose fertility can be expected to be similar, in order to study how much of the declining macro-TFR for all immigrant women is due to changed composition. Thus, this paper does not test the hypotheses on migrant fertility presented above. Rather, it contributes to the literature by showing how knowledge from micro-studies can be used to investigate changes at the macro-level.Uncovering factors that affect individual immigrant women’s fertility, which has been the focus in much of the literature in this field, can certainly be used in order to understand macro-trends in immigrant TFR. However, it is not sufficient unless changing composition of immigrant women is also taken into account. For instance, if micro-studies show that immigrant women’s fertility tends to decline by their duration of stay, this does not necessarily translate into a declining TFR for all immigrant women over time unless the What-if scenarios and a formal decomposition. First, in the what-if scenarios, the composition of immigrant women (by eight origin areas and four durations of stay) is allowed to change like it actually did, while the fertility in each subgroup is kept constant at 2000 levels—and vice versa. Second, a decomposition based on Kitagawa , and to what extent is it due to changed fertility within subgroups of immigrant women? The methods also identify subgroups that are driving the change.The two methods are demonstrated using register data from Norway. Norway may be a good case for several reasons: As Fig. The data are from Norway’s population register, which includes complete cohorts of all immigrant women and all their live births in Norway. Immigrants are defined as people born abroad to foreign-born parents and grandparents and who have immigrated to Norway in order to stay for at least 6 months, with legal permission to stay. This study included 207,078 births to immigrant mothers (2000–2017) and a total of 2,773,274 person-years of immigrant women aged 15–49 . Due to insufficient information about the mothers, 179 births were excluded from the sample.As shown in Fig. In this period, both the number and the composition of immigrant women changed markedly. After the European Union enlargement in 2004, a substantial number of women from the new eastern member states migrated to Norway. Immigration from other parts of the world also increased. Figure 3The left panels in Fig. All the four duration-of-stay groups have seen large increases, whereas the proportions in each group have been relatively stable over the last decades (lower right panel). Thus, the share of women from traditionally high versus low-fertility areas of the world has not changed very much, nor has the distribution by duration of stay. This suggests that changed composition by origin area or duration of stay may not be the main driver behind the immigrant TFR decline.The total fertility rate (TFR) is the core measure in these analyses. TFR is probably the most widely used fertility measure worldwide .TFR is often interpreted as “number of children per woman”. This interpretation is not necessarily fruitful when TFR is used to analyse immigrant fertility. As several authors have noted  does not necessarily imply convergence in another (e.g. completed family size/cohort fertility)  who are in group i.What-if scenarios can illustrate how these three main features have affected the general immigrant TFR. In these scenarios, certain factors are kept constant while others are allowed to change over time. First, the composition of immigrant women (by origin area and duration of stay) is allowed to change like it actually did from 2000 to 2017 while fertility within each of the 32 subgroups is kept constant at the 2000 level. Second, the composition of immigrant women is kept constant while fertility within each subgroup is allowed to change. This method takes advantage of the fact that TFR across several groups of women can be calculated in this way:ait constant at the 2000 level while letting wait change. This gives the what-if scenario where only composition is allowed to change. Letting ASFRait change while the wait is kept constant gives the scenario where only fertility within each group is allowed to change. In this scenario, the number of women in each age group is fixed as well.Using the last term of this equation, it is possible to keep ASFRIt is also possible to allow fertility to change only within certain groups of immigrant women, keeping both composition and other groups’ fertility constant. This is done to investigate the separate effect of changed fertility among newly arrived immigrant women.R, then A and B. In this case, the changes are decomposed intow sums to one over all i.What-if scenarios are well suited to answer hypothetical questions. However, the estimated hypothetical changes in the what-if TFR paths do not necessarily add up exactly to the real TFR change in the same period. A decrease in TFR has one rate component (assuming no change in composition) and one composition component (assuming no change in rates), and also an interaction component reflecting changes in both rates and composition  was allowed to change like it actually did between 2000 and 2017. The resulting what-if TFR for all immigrant women is shown in the upper left panel of Fig. The upper right panel of Fig. Many of Fig. The decrease among the newly arrived seems most pronounced among women from high-fertility areas of the world Fig. . The effwithin the subgroups, while 7% is due to changed composition by origin area and duration of stay  also plays a role; 27.5% of the total decline can be attributed to this group. About half of this (13.4%) is due to lower fertility among Asian immigrants.To sum up, both the what-if scenarios and the decomposition suggest that the decline in immigrant TFR in Norway to a large extent is due to the newly arrived immigrant women having a lower fertility now than the newly arrived had in 2000.Some of this decrease may be due to changed selection. For instance, reasons for migration may have changed. Reason for immigration is recorded at immigrants’ first arrival in Norway (unless they are Nordic citizens). Research from other countries has shown that fertility tends to differ by reason for migration, and women who migrate for family reasons often have relatively high fertility . Moreover, Fig. 4First, the trend could be age of arrival is found to be crucial for an immigrant woman’s fertility, indicating that immigrants who arrive as children may adapt faster [shown for instance by Adserà et al. , changed composition by duration of stay  and changed composition by reason for immigration (which matters according to the selection hypothesis), fertility changes are still clearly seen among immigrant women in Norway. In particular, TFR declined markedly among newly arrived family migrants, particularly from Asia (and Latin America). This seems to be related to fertility trends in origin areas. Such origin area trends are sometimes overlooked in studies and theories of immigrant fertility. Although the newly arrived immigrant women grew up in the same origin areas as those who moved to Norway one or two decades ago, they grew up in a different time. And as societies change over time, so does socialization.This study has relevance for research on migrant fertility as well as for policy. First, it proposes methods to investigate changes in the overall immigrant TFR in a country by disentangling composition effects from the effects of changed fertility within subgroups. The methods can be used in any context with adequate data on births and mother’s characteristics.of arrival as well as time since arrival, particularly when there have been clear trends in origin area fertility. For instance, one should be cautious when pooling immigrant women over many arrival cohorts unless changing fertility in origin is controlled for.Second, the results show that the decreased immigrant TFR in Norway is mainly driven by lower fertility among newly arrived women—possibly partly reflecting declining fertility trends in their countries of origin. This may remind migration researchers to look for explanations of changed immigrant fertility beyond the destination country and characteristics of the individual migrants. Moreover, it points to the need for immigrant fertility studies to take into account time Third, this study can be a reminder for policy makers and others not to draw too quick conclusions about the effect of domestic policies on immigrant TFR. Although an immigrant woman’s fertility often declines with her duration of stay, due to, for instance, successful integration, this does not necessarily translate into a declining TFR for all immigrants.Fourth, the results of this study also point to the future: if changed fertility in origin areas is a driver behind the fertility decline among many Non-Western newly arrived migrants, and if fertility continues to fall in important origin areas—which the UN projects for high-fertility parts of the world UN —we may eImmigrants’ total fertility rate has declined in many Western countries over the last decades. This may be due to several factors, such as successful integration, changed composition of immigrants by origin area, or other reasons. Whereas existing research has focused mainly on individual immigrant women’s fertility behaviour and variations between groups of immigrant women, there is much less evidence on the mechanisms behind changes in the aggregated fertility level of all immigrants in a country. This paper aims at filling the knowledge gap by proposing two methods—what-if scenarios and a formal decomposition—to disentangle the effect of changed composition from the effect of changed fertility within subgroups.Both methods are demonstrated using data from Norway, where immigrant TFR declined from 2.6 in 2000 to below 2.0 in 2017. The effect of changed composition by origin area and duration of stay was disentangled from the effect of changed fertility within subgroups (by origin area and duration of stay). The results show that although an immigrant women’s fertility often declines with her duration of stay, this is not the main reason for the TFR decrease, nor is changed composition by origin area. Instead, most of the TFR decline is due to changed fertility within the subgroups, most notably among the newly arrived immigrant women, who have lower fertility now than the newly arrived had 15–20 years ago. In particular, lower fertility among newly arrived immigrant women from Asia accounts for 27.6% of the TFR decline among all immigrant women.This fertility decline among newly arrived women was further decomposed by reason for migration, and family migrants appear to provide a key: their share among all newly arrived immigrant women declined in this period, and so did their fertility. After investigating several possible reasons for their fertility decline, such as education level, age at migration, number of pre-migration births and residential segregation, I suggest that a large part of the fertility decline among newly arrived family migrants from Non-Western parts of the world may be a reflection of fertility decline in origin areas. Consequently, if fertility continues to decline in high-fertility countries, this may bring about further fertility declines among newly arrived immigrants from these countries in Western societies.Supplementary material 1 (PDF 273 kb)Below is the link to the electronic supplementary material.


Uric acid (UA) is the end product of purine nucleotide metabolism in the human body. Hyperuricemia is an abnormally high level of UA in the blood and may result in arthritis and gout. The prevalence of hyperuricemia has been increasing globally. Epidemiological studies have shown that UA levels are positively correlated with cardiovascular diseases, including hypertension, atherosclerosis, atrial fibrillation (AF), and heart failure (HF). Hyperuricemia promotes the occurrence and development of cardiovascular diseases by regulating molecular signals, such as inflammatory response, oxidative stress, insulin resistance/diabetes, endoplasmic reticulum stress, and endothelial dysfunction. Despite extensive research, the underlying molecular mechanisms are still unclear. Allopurinol, a xanthine oxidase (XO) inhibitor, has been shown to improve cardiovascular outcomes in patients with HF, coronary heart disease (CHD), type 2 diabetes (T2D), and left ventricular hypertrophy (LVH). Whether febuxostat, another XO inhibitor, can improve cardiovascular outcomes as well as allopurinol remains controversial. Furthermore, it is also not clear whether UA-lowering treatment (ULT) can benefit patients with asymptomatic hyperuricemia. In this review, we focus on the latest cellular and molecular findings of cardiovascular disease associated with hyperuricemia and clinical data about the efficacy of ULT in patients with cardiovascular disease. Uric acid (UA) is the end product of purine metabolism in higher animals, such as humans and great apes. Under physiological conditions, UA synthesis and excretion are balanced in the body. Once this balance is disturbed, it leads to hyperuricemia. Normally, male UA levels greater than 7 mg/dL or female UA levels greater than 6 mg/dL are considered to be hyperuricemia . HoweverAn increasing number of clinical studies show that allopurinol can improve cardiovascular outcomes in patients with heart failure (HF), CHD, type 2 diabetes (T2D), and left ventricular hypertrophy (LVH) . CompareThis review focuses on the underlying mechanisms of cardiovascular disease associated with hyperuricemia and the efficacy of ULT in patients with cardiovascular disease.UA is the final product of dietary purines. Existing evidence suggests that UA has a dual-face role in some cardiovascular and cerebrovascular diseases. On the one hand, UA has antioxidant activity and can scavenge reactive oxygen species (ROS). As one of the main endogenous antioxidants in the human body, UA contributes up to 60% of the plasma antioxidant capacity, which can protect cells from oxidative stress . The molIn recent years, a lot of progress has been made on the relationship between UA and oxidative stress and its molecular mechanism. The physiological concentration of UA decreased oxidative stress–induced malondialdehyde and protein carbonyl contents, promoted superoxide dismutase (SOD) activity, and inhibited the formation of ROS in chicken embryo cardiomyocytes . The undIn short, previous studies have confirmed that UA has both antioxidant and pro-oxidant effects in vivo. This dual effect of UA has also been confirmed in cardiomyocytes. The latest experimental studies demonstrate that the antioxidation of UA may be involved in regulating the Nrf2-ARE, ERK/p38, and PI3K/Akt signaling pathways.UA has been a focus of research not only for its role in oxidative stress, but also for its relation to various inflammatory diseases. Atherosclerosis is a chronic immuno-inflammatory cardiovascular disease. A large body of evidence suggests that elevated UA levels are strongly associated with the occurrence and development of atherosclerosis. High intracellular UA concentrations promote the expression of inflammatory markers, such as nuclear factor κB (NF-κB), growth factors, vasoconstrictive substances , and chemokines via activating mitogen-activated protein kinases (MAPK) . AdditioThe activation of inflammasomes plays a critical role in a variety of chronic inflammatory diseases. Recently, many studies have found that sUA can effectively activate inflammasomes in the cardiovascular system. The continuous activation of inflammasomes aggravates the inflammatory response and damages the cardiovascular system. Studies by Wang et al. report that UA can activate nod-like receptor protein 3 (NLRP3) inflammasomes and damage mitochondria, resulting in cellular damage of H9c2 cells . In addiIn conclusion, UA has been shown to promote inflammation in a variety of cells. Hyperuricemia can promote the development of atherosclerosis by regulating inflammatory signal pathways, such as NLRP3-inflammasomes, macrophage M1/M2 polarization, and hs-CRP, and ULT can significantly reverse the formation of atherosclerotic plaques. Inhibition of UA-induced NLRP3 inflammasome activation may be a new therapeutic target for atherosclerosis.Insulin resistance is closely related to diabetes, obesity, hyperlipidemia, hypertension, hyperuricemia, and other metabolic disorders. Current studies confirm that oxidative stress and inflammation may be the pathophysiological basis of insulin resistance. Hyperuricemia can promote oxidative stress in many cell lines. The rise of ROS level can induce insulin resistance. Oxidative stress may be the cause of insulin resistance–related cardiovascular complications because overgenerated ROS and insulin resistance may lead to cardiac dysfunction . Our teaClinical studies have shown a link between hyperuricemia and diabetes ; howeverCardiomyocyte apoptosis is one of the pathogeneses of myocardial anatomical reconstruction. Oxidative stress and endoplasmic reticulum stress are the key factors promoting apoptosis, which are involved in the pathogenesis of many diseases, including cardiovascular diseases. UA triggers oxidative stress and endoplasmic reticulum stress to signal the network to induce endothelial dysfunction via activating the protein kinase C (PKC) pathway in human umbilical vein endothelial cells (HUVECs) . The lat2, endothelium-derived hyperpolarizing factor, etc.) and vasoconstrictors  (–)  . Vasodiltc.) (–) . ONOO– ixidation . In addixidation . Furtherxidation . All theEndothelial dysfunction plays a critical role in the development and progression of atherosclerosis, leading to serious cardiovascular events. Experimental studies show that high UA aggravates the inflammation response and oxidative stress and, thus, leads to endothelial dysfunction . AdditioElevated sUA is strongly associated with hypertension, but the mechanism is not clear. Hyperinsulinemia induced by insulin resistance enhances renal sodium reabsorption, which may lead to hypertension . EndotheUricase/Uox knockout male mouse model  . AnotherAlthough many clinical studies confirm that elevated sUA levels are strongly and independently associated with the occurrence and development of coronary atherosclerosis, the severity of coronary artery lesions and cardiovascular and all-cause mortality, the molecular mechanism of UA promoting atherosclerosis is still unclear. Plaque morphology, endothelial dysfunction, oxidative stress, and inflammation play a critical role in the development and progression of atherosclerosis, leading to serious cardiovascular events . OpticalIn brief, hyperuricemia is a potential risk factor for CHD. The elevated sUA may lead to endothelial dysfunction through inflammation and oxidative stress and the formation of unstable lipid plaque in the coronary artery, which eventually leads to the occurrence of atherosclerosis. Therefore, lowering the level of UA is crucial in the prevention and treatment of CHD  and increasing UA excretion . Current studies confirm that ULT has a good effect in young hypertensive patients, but the effect on CHD, AF, and HF has not achieved satisfactory clinical results. In terms of drug selection, previous studies have suggested that febuxostat is more effective and safer than allopurinol. Recent studies have shown that ULT made no difference in the occurrence of primary end-point events . However, cardiovascular death appeared to be higher in the febuxostat group compared to the allopurinol group . TherefoNotably, sodium glucose cotransporter 2 inhibitors  can effectively reduce sUA level by accelerating the excretion of UA . DapagliCollectively, the relationship between hyperuricemia and cardiovascular disease is becoming clearer, which is attributed to the study progress of UA. First, Tomiyama et al. found that hyperuricemia increased arterial stiffness and inflammation, which may be involved in the risk of development of hypertension. Second, UA induces NLRP3 inflammasome-dependent inflammation activation via the AMPK-mTOR-mROS and HIF-1α pathways. In contrast, decrease of UA level promotes the activation of AMPK and inhibits the formation of atherosclerotic plaque. Furthermore, UA significantly enhances the expression of Kv1.5 protein and enhances Akt and HSF1 phosphorylation, leading to increased Hsp70 expression. This result suggests that inhibition of the Akt-HSF1-Hsp70 pathway may be a novel therapeutic approach against AF in patients with hyperuricemia. Last but not least, high UA induces insulin resistance in cardiomyocytes through the ROS-IRS1/Akt phosphorylation pathway. High UA-induced insulin resistance may be an important pathological mechanism of HF.A large number of studies have shown that UA levels are positively correlated with hypertension, CHD, AF, and HF , the Natural Science Foundation of Fujian Province (2020J01010) and the Xiang’an Hospital of Xiamen University (PM201809170002).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


We sought to evaluate its diagnostic performance in Cameroun.this community-based study took place in a sub-urban area, from November 2015 to April 2016. Adults aged ≥19 years underwent a clinical assessment, including the STOPBANG and the Epworth sleepiness scale (ESS) questionnaires. A respiratory polygraph (RP) was performed on a randomly selected sample. Diagnosis performance included sensitivity (Se), specificity (Sp), and positive and negative predictive values (PPV and NPV). An association was sought between STOPBANG and OSA features.2. For OSA screening (apnea-hypopnea index (AHI) ≥5), the STOPBANG score at threshold 3 obtained: Se=82.9%, Sp=34.4%, PPV=45.9% and NPV=75.0%. For moderate-to-severe OSA (IAH ≥15), these values were 93.3%, 31.1%, 18.9% and 96.4% respectively. Furthermore, STOPBANG-based high risk of OSA correlated with AHI  and oxygen desaturation index . There was a non-significant association with ESS .a total of 3033 were interviewed, of whom 102 had a RP. Their mean age was 49.1±17.9 years, the sex ratio was 1 and the mean body mass index 29.1±6.1 kg/min this Cameroonian population, the STOPBANG diagnostic performance did not differ from the original Caucasian one. It could therefore be proposed on a larger scale, since obesity and other OSA risk factors are increasing in SSA. Obstructive sleep apnea-hypopnea syndrome (OSAHS) is frequent in the adult population. Its prevalence ranged in historical Western and Asian studies between 3 to 7% and 1 to 3% for men and women respectively . HoweverThe optimal diagnosis of OSAHS is easy and reliable, but requires devices that are not uniformly affordable, especially in the sub-Saharan African (SSA) context, leading to under diagnosis and difficulties to assess the real burden of this condition. Besides this limitation, we can assume that there is an epidemiological increase in OSAHS incidence and prevalence in SSA, consistent with the global expansion of chronic non-communicable diseases (NCD). Cardiovascular diseases, diabetes and obesity increased their prevalence over the last 20 years -26, and Setting and period: this cross-sectional study took place in Bandjoun, a sub-urban area and headquarters of the Koung-Khi division, West Region, Cameroon. With a 353 km2 area and 119,251 inhabitants, Bandjoun had 337 inhabitants/km2 in 2015. The study was conducted over a 6-months period, from November 2015 to April 2016. Adults aged ≥19 years living in the study area and with no cognitive nor sensory impairment were invited to participate.Sampling: for the overall study sample, a 2-levels clusters sampling was performed. At the first level, we randomly selected 6 health areas out of the 13 in Bandjoun health district. At the second level, a given number of households were randomly selected in each health area, with a sampling rate ranging from 3 to 14, depending on the population density. Then, all eligible subjects in each selected household were invited to participate in the survey. For the nocturnal respiratory polygraph (RP) group composition, we applied an additional random sampling among the overall sample, so that 20% of participants with high risk of OSAHS (HR-OSAHS) and 3% of those with low risk of OSAHS were selected.Data collection and measurements: seventh year trained medical students collected data, during a physical interview with each participant and using a comprehensive computerized questionnaire. Each subject or one of his relatives reported socio-demographic data, medical history, and symptoms. A physical examination was performed to collect anthropometric data and any other abnormality. We measured the height using a wooden rod of local manufacture, and the weight using an electronic weighing scale. Body mass index (BMI) was subsequently calculated using the formula Weight/ (Height)2. The blood pressure was given by an electronic sphygmomanometer, and other measurements (neck and waist circumference) by a usual tape. The daytime sleepiness was assessed using the Epworth Sleepiness Scale (ESS). This included 8 items that explored different daily situations. Each item was coted 0 to 3, for a total score of 0 to 24. Excessive daytime sleepiness was defined by an ESS score >10 [core >10 .2 (obesity), Age >50 years, Neck circumference >40cm and male Gender. Each item coted “Yes” worth 1 point, and the score is the sum of points. In the original population, the STOPBANG sensitivity at threshold 3 was 93% for moderate OSAHS (apnea hypopnea index (AHI)=15-30/h) detection and 100% for severe one (AHI >30/h) [The STOPBANG score was calculated after the interview. This screening tool was developed in a pre-operative Caucasian population, and includes 8 items with “Yes” or “No” answers modality: Snoring, daytime Tiredness, Observed apnea, high blood Pressure (HBP), Body mass index (BMI) >30kg/mI >30/h) , 28. ForData management and analysis: for the main epidemiological study, the expected global sample size using Epi Info 7 was 1859, based on 2% OSAHS prevalence, 1% precision, 1.3 design effect and 10% predicted non-response rate. The number of nocturnal RPs was estimated as described above (Sampling section). We used Epidata entry 3.1 software for data collection, and IBM-SPSS Version 20 on Windows  for analysis. Categorical variables were presented as numbers and proportions, and quantitative variables as means and standard deviations (SD). We compared polygraphy and non-polygraphy groups using Chi square or Fisher tests for factors, and T Student or Mann Withney tests for continuous variables. The same tests were used to find out correlations between HR-OSAHS and other features. Power analysis was performed for the STOPBANG sensitivity, using the pwr.p.test function of R version 3.6.0, considering 80% sensitivity as reference. A 5% p-value level was used during the whole analysis process.Operational definitions: OSAHS was defined as AHI ≥5 events per hour. Moderate to severe OSAHS (MS-OSAHS) was defined as AHI ≥15 or more. The high risk of OSAHS was defined as the presence of at least 3 “yes” responses to STOPBANG questionnaire. The predictive values  were determined by the standard equations.Ethic statement: the National Ethics Committee for Human Health Research in Cameroon and the West Region’s health authorities approved the study. We further obtained a recruitment authorization from local authorities in each visited area. Each participant gave a verbal consent, after awareness of the information form read by the investigator. This verbal procedure was imposed by the working conditions: investigators had to cover great distances between houses, districts and villages; they collected data directly on computer and did not carry paper. Furthermore, some participants (illiterate and/or elder) were unable to read or fully understand written form.Recruitment of subjects: initially, 3520 subjects were invited to participate to our study, of whom 154 were selected for polygraphs and 102 finally presented an exploitable RP, as shown on Study population: compared with the other group, participants who benefited from a RP were significantly older , they had a higher frequency of hypertension , diabetes mellitus  and smoking . They also had a higher mean BMI . There was non-significant men predominance in the polygraph group. These characteristics are represented on STOPBANG performance: numbers and frequencies for OSAHS and MS-OSAHS according to the STOPBANG status are summarized on Principal findings: some characteristics  of the 102 polygraph group’s subjects differed from those of the global sample surveyed. The prevalence of OSAHS in the RP group was 40.2%. Concerning STOPBANG diagnostic performance for global and moderate to severe OSAHS respectively, sensitivity was of 82.9 and 93.3%, specificity was 34.4 and 31.0%, PPV was 45.9 and 18.9% and NPV was 75.0 and 96.4%. The STOPBANG-based HR-OSAHS was associated with AHI, oxygen desaturation index and ESS.External validity: the higher age, BMI and hypertension rate in the VPG group could lead to an overestimation of diagnostic performance, since those 3 features are part of the STOPBANG questionnaire. However, in the main STOPBANG validation study, the characteristics of patients in polysomnography group (177 patients) were even more at risk than those of our patients: average BMI =30±7kg/m2, average age =56±13 years, sex ratio H/F=1.01 [H/F=1.01 . Our OSAInternal validity: our study presented some limitations. The West Region is known to have a high-fat diet, leading to suspected higher overweight and obesity prevalence. This population is therefore probably not representative of the country. Our resulting RP sample was therefore probably even less representative, which makes the extrapolation of our results tricky. The number of RPs performed was limited and may have contributed to the disruption of our results. The high refusal and withdrawal/unavailability rates (18.8%) were one of the causes of this limited number of polygraphies and could partly explain the differences between RP group and overall sample. This could occur through a self-selection phenomenon: the more symptomatic, older, smoker and obese subjects could be more health-concerned and accept more willingly to undergo screening tests. The consequence of this self-selection may have overestimated the sensitivity of our screening tool. The high frequency of non-exploitable RP records (18.4%) may also have skewed our results. This could be explained by a progressive experience acquirement for the investigators, accidental sensors removal during sleep and unexplained interruptions of signal capture. However, the randomness of these technical flaws should minimize their effect on the STOPBANG diagnostic performance. The calculated power of STOPBANG sensitivity was low for OSAHS and high for MS-OSAHS, probably due to a larger clinical gap (between measured sensitivity and reference) for the latter. The positive association found with AHI and oxygen desaturation index was an additional argument in favor of STOPBANG effectiveness in predicting OSAHS. Strengths of our study included the random sampling and the number of participants enrolled for the overall study. In our knowledge, this was the first community study using a nocturnal polygraphy in Cameroon.Key message: despite the limitations, our STOPBANG score performance was close to the original one, especially in MS-OSAHS detection, which is the main target for treatment. However, these limitations should lead to caution and encourage additional studies with larger and more representative populations.In this sub-Saharan African community-based validation study, the STOPBANG performance for OSAHS screening was comparable to that previously described in Caucasian populations. Physicians in SSA could therefore be encouraged to use this simple, costless, and efficient tool, for the OSAHS screening on selected patients. Obesity and other cardiovascular risk factors frequently associated with OSAHS are increasing in SSA, and the affordability of sleep disorders diagnosis devices is still very low. However, there is still need for diagnostic devices availability, to conduct reliable polygraphy-based community and clinical studies.Studies on obstructive sleep apnea-hypopnea syndrome (OSAHS) are scarce in sub-Saharan Africa;The effectiveness of the STOPBANG score in screening OSAHS has been established in western population.The prevalence of OSAHS was high in this sub-urban Cameroonian population but was consistent with national and sub-regional estimation;The STOPBANG score for OSAHS screening in this SSA population, seems to be as effective as in the Western settings.