Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
thereby , reconstruction of the last common ancestor ( lca ) to all mollusks , the so - called hypothetical ancestral mollusk , has been hampered by difficulties in recovering fossils of unambiguous molluscan stem species and by the lack of a general agreement concerning the relationships of the various molluscan class - level taxa to each other . as a consequence ,
morphology - based analyses have suggested either one or the other of the sclerite - bearing but shell - less aplacophoran clades ( neomeniomorpha or chaetodermomorpha , respectively ) as the earliest molluscan offshoot [ 8 , 9 ] , a monophyletic aplacophora as sister group to all remaining mollusks ( the testaria ) , or a polyplacophoran - aplacophoran assemblage ( aculifera ) as sister to all other mollusks with a primarily univalved shell ( conchifera ) [ 11 , 12 ] .
this controversy may soon be settled , however , since two phylogenomic studies have independently confirmed the latter concept , whereby both recovered a monophyletic aplacophora as sister group to polyplacophora ( chitons ) within aculifera [ 4 , 5 ] . in the light of this phylogenetic framework ,
the recent description of a cylindrical ( i.e. , worm - shaped ) sclerite- and shell - bearing paleozoic mollusk   and the results of integrative molecular - paleontological studies [ 13 , 14 ] have been considered as evidence for the presence of seven or eight shell plates in the lca of crown - group aculiferans . if correct , this implies that the body plan of recent aplacophorans is the result of secondary simplification and thus a derived condition [ 6 , 14 ] . despite additional descriptions of fossils that exhibit a mixture of polyplacophoran- and aplacophoran - like features [ 15 , 16 ]
this may be due to the overall paucity of well - preserved paleozoic fossils that undoubtedly can be assigned to the aculiferan lineage , the uncertainty as to whether or not some early ( cambrian or precambrian ) fossils [ 17 , 18 ] indeed represent crown- or stem - group mollusks , and the fact that solid morphological and developmental evidence from recent aplacophoran representatives is still largely lacking
. the few reports of individual aplacophoran larvae and postlarvae have shown that these animals may bear six or seven rows of papillae , sclerites , or sclerite - secreting cells [ 1921 ] , but these studies found no further support by gross morphological developmental studies of two neomeniomorph representatives [ 22 , 23 ] .
the muscular architecture of mollusks is intimately associated with the existence , number , and arrangement of shells in the respective taxa . in polyplacophorans ,
the myoanatomy is highly complex [ 7 , 25 ] ( figures 1a and 1c ) and several components , such as a laterally positioned enrolling muscle and a dorsal rectus system that spans the longitudinal axis of the animal , have been widely considered as defining morphological features ( autapomorphies ) of this taxon . in stark contrast to the sophisticated polyplacophoran myoanatomy , aplacophoran representatives have a much simpler muscular organization that , together with the body wall musculature , mainly comprises serially repeated dorsoventral muscles ( figures 1b and 1d ) .
accordingly , a scenario that suggests a shell plate - bearing aculiferan lca with polyplacophoran - like musculature implies drastic secondary simplification of the muscular body plan of aplacophoran mollusks . since ontogenetic data may provide important insights into the evolutionary history of a given taxon [ 26 , 27 ] , we investigated the development of a model neomeniomorph aplacophoran , wirenia argentea , from hatching of the larvae until after metamorphosis . in comparing myogenesis in wirenia with that of a polyplacophoran ( leptochiton asellus )
, we found striking similarities in the muscular organization of both species ( see table 1 for a summary of major larval and adult muscle systems known for the various molluscan lineages ) , including the presence of a rectus muscle ( figures 2a2d ) , so far only known from polyplacophorans , and a laterally positioned enrolling muscle ( figures 2a2h ) .
both systems are retained in adult polyplacophorans but are lost during wirenia postlarval development ( note that some neomeniomorphs do exhibit distinct enrolling muscles as adults [ 28 , 29 ] ) . although homology between the polyplacophoran and neomeniomorph enrolling muscles has been questioned , their similar position in the respective animals and , in particular , their identical mode of ontogenetic formation as independent muscle system ( and not as a thickened derivative of the body wall musculature , as proposed earlier for the aplacophoran taxa ) argue strongly for their common evolutionary origin and thus for the presence of such a system in the lca of both clades . aside from these muscles
both systems are only transiently present in advanced larvae , and neither has a counterpart in either the polyplacophoran or the neomeniomorph adult body plan . as with the rectus and the enrolling muscles , the identical positions of the ventrolateral and the ventromedian muscles in wirenia and leptochiton larvae , together with their identical positions relative to other muscles , clearly suggest that these respective muscles are homologous between the two species ( see   for a recent overview on homology theory and assessment ) . earlier , we had already found the ventrolateral system in larvae of another polyplacophoran , mopalia muscosa , but had overlooked the ventromedian muscle .
reinvestigation of the original 3d data set , however , unambiguously revealed such a muscle also in mopalia ( data not shown ; available on request ) .
accordingly , it appears highly likely that the ventrolateral and the ventromedian muscles together with the enrolling and the rectus muscle were all part of the muscular toolkit of the lca of polyplacophorans and neomeniomorphs , and that the simple myoanatomy of adult wirenia is a derived , secondary condition .
formation of the eight sets of dorsoventral muscles in polyplacophorans passes through a transitory stage of multiple individual myocytes that appear synchronously   ( figure  2e ) and give rise to the first seven paired shell muscle units ( while the eighth set forms considerably later , together with the most posterior shell plate ) .
in wirenia , seven pairs of dorsoventral muscles develop simultaneously ( figures 3a3e ) and differentiate further in later stages ( figure  2f ) .
a gradual numerical increase of the dorsoventral muscle sets was observed only after metamorphosis ( figure  3f ) .
accordingly , both neomeniomorphs and polyplacophorans exhibit a transient stage of seven - fold seriality in the arrangement of these muscles . despite the different ontogenetic pathways that lead to this seven - fold seriality ( fusion of multiple myocytes in polyplacophorans versus simultaneous formation in wirenia )
, this seven - fold seriality appears to be a reoccurring pattern , at least in aculiferan mollusks ( unfortunately , the ontogenetic sequence of the formation of the eight pairs of dorsoventral muscles in monoplacophora is still unknown ) .
this is well in line with the description of the seven - shelled fossil kulindroplax , as well as with the serially arranged sclerites or papillae of some recent aplacophorans [ 1921 ] , and lends further support for an aculiferan lca with a seven - fold seriality of epidermal hardparts and the associated musculature .
this implies that the eighth set of dorsoventral muscles of recent polyplacophorans is a derived condition .
the late formation of the most posterior shell plate and associated musculature in polyplacophorans [ 7 , 31 ] may well be considered as ontogenetic testimony of such a scenario .
the rudimentary data on myogenesis ( and development in  general )   of the second aplacophoran taxon , the chaetodermomorpha , does not allow for definite conclusions concerning the presence of neomeniomorph- and/or polyplacophoran - like features such as the rectus or the ventromedian muscles in the lca of this taxon .
however , the ring musculature in the body wall of both aplacophoran clades , which is also rudimentarily present in the apical region of polyplacophoran larvae   ( figure  2 ) , may constitute an aculiferan apomorphy uniting polyplacophora , neomeniomorpha , and chaetodermomorpha ( table 1 ) .
this , together with the cylindrical shape of the aplacophorans and the polyplacophoran larva as well as the fossil kulindroplax , argues for a worm - like body shape of the lca of aculifera , rendering the dorsoventrally flattened appearance of recent polyplacophorans a derived condition .
the paired lateral longitudinal muscle in the larva of the chaetodermomorph chaetoderma   may correspond to either the enrolling or the ventrolateral muscle of larval polyplacophorans and neomeniomorphs ( table 1 ) , which would further support the inclusion of chaetodermomorpha within aculifera .
the fact that kulindroplax shares morphological features not only with polyplacophorans but also with recent chaetodermomorphs , including the absence of a pedal pit and the position of the gills , likewise supports such a scenario .
whether or not a monophyletic aculifera will stand the test of future phylogenetic analyses or whether chaetodermomorpha , despite these shared morphological characters , will be proven to have different affinities   remains to be seen .
the transient expression of typical polyplacophoran - like muscles in the wirenia larva , however , strongly suggests that at least neomeniomorph aplacophorans stem from an ancestor with polyplacophoran - like features that most likely also included seven shell plates .

Answer:
summarymollusca is an animal phylum with vast morphological diversity and includes worm - shaped aplacophorans , snails , bivalves , and the complex cephalopods [ 1 ] .
 the interrelationships of these class - level taxa are still contentious [ 2 , 3 ] , but recent phylogenomic analyses suggest a dichotomy at the base of mollusca , resulting in a monophyletic aculifera ( comprising the shell - less , sclerite - bearing aplacophorans and the eight - shelled polyplacophorans ) and conchifera ( all other , primarily univalved groups ) [ 4 , 5 ] . the aculifera concept has recently gained support via description of the fossil kulindroplax , which shows both aplacophoran- and polyplacophoran - like features and suggests that the aplacophorans originated from a shelled ancestor [ 6 ] , but the overall morphology of the last common aculiferan ancestor remains obscure . here
 we show that larvae of the aplacophoran wirenia argentea have several sets of muscles previously known only from polyplacophoran mollusks .
 most of these are lost during metamorphosis , and we interpret them as ontogenetic remnants of an ancestor with a complex , polyplacophoran - like musculature .
 moreover , we find that the first seven pairs of dorsoventral muscles develop synchronously in wirenia , similar to juvenile polyplacophorans [ 7 ] , which supports the conclusions based on the seven - shelled kulindroplax .
 accordingly , we argue that the simple body plan of recent aplacophorans is the result of simplification and does not represent a basal molluscan condition .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
in this case report , we describe a case of asherman 's syndrome treated with adult autologous stem cells for endometrial regeneration that resulted in conception after in vitro fertilization - embryo transfer ( ivf - et ) .
the basis of this case is that endometrium is a dynamic , cyclically regenerating tissue , a unique model of physiological angiogenesis in adults .
angiogenesis results either from sprouting of new vessels through recruitment of local endothelial cells from neighbouring blood vessels and/or by endothelial progenitor cells circulating in the peripheral blood after release from the bone marrow.[14 ] bone marrow stem cells also contribute to regeneration of the endometrium . on the basis of these facts ,
her past treatment included a dilatation and curettage ( d and c ) in february 2005 .
she presented to us with infertility and scanty menstruation since her d and c. her first transvaginal ultrasound scan on day 3 of the menstrual cycle revealed normal size retroverted uterus with homogenous myometrium and thin single line endometrium , but intact endometriomyometrial junction .
the left ovary measured 2.52  2.51  3.04 cm , had two antral follicles and a hemorrhagic cyst , and was adherent to uterus posteriorly .
right ovary measured 2.55  1.22  1.84 cm and had only one antral follicle .
doppler studies showed very poorly vascularised ovaries , even with minimum wall filter , pulse repetition frequency of 0.3 , and gains -0.8 .
a repeat scan on day 14 revealed that hemorrhagic cyst in left ovary had regressed partially .
right ovary showed a follicle of 20 mm which on color doppler showed vascularity covering more than three - fourth of the follicular circumference with resistance index ( ri ) of 0.47 and peak systolic velocity ( psv ) of 11.23 cm / s , but the endometrium was only 3.2 mm with branches of spiral vessels seen only up to endometrio - myometrial junction .
follow - up scan after three days still showed the same endometrial picture though follicle had ruptured .
midluteal ultrasound scan ( ninth day post ovulation ) showed that endometrium had failed to grow even during secretory phase , despite corpus luteum with vascular ring covering more than half of the corpus luteal circumference with ri of 0.43 and psv of 10.43 cm / s on right side .
severe endometrial adhesions were seen , which were cut [ figures 1 and 2 ] .
hysteroscopic picture - endometrial adhesions postadhesiolysis hysteroscopic picture iucd - cu t was placed to maintain surgically established patency of the endometrial cavity .
she was treated with cyclical estrogen and progesterones with ethinyloestradiol 0.05 mg from fifth to 25 day of the cycle and with medroxy progesterone acetate 10 mg from 20 to 25 day for 6 months to obtain a functional endometrium . during this period , she had withdrawal bleeding , which was scanty .
ultrasound assessment of the endometrium in the following cycle showed no growth of the endometrium in the periovulatory and secretory phase of the menstrual cycle despite normal follicular development , rupture , and corpus luteum formation .
thin endometrium after removal of iucd in preovulatory period due to poor endometrial development , she was advised surrogacy with ivf .
her fsh on day 3 of cycle was 19.70 iu / ml with an antral follicle count of 2 . in view of poor ovarian reserve ,
she was given oral oestradiol valerate tablets in increasing doses from 4 mg daily for 3 days , followed by 6 mg daily for another 3 days , and then 8 mg daily for a total of 25 days along with aspirin 75 mg daily for endometrial preparation .
ultrasound scans were done intermittently to assess the endometrium , but it never reached a thickness more than 3.6 mm .
this hormone replacement therapy cycle was repeated for 6 months without improvement of the endometrium . based on reports of adult autologous stem cells applications for regeneration of
injured cartilage and cardiomyocytes in cardiac infarction , it was thought that use of stem cells for regeneration of endometrium was worth trying , especially because endometrium naturally has a regenerating capacity .
if the basal layer of the endometrium is repaired and further stimulated , it should increase in thickness .
on june 15 , 2009 , her bone marrow aspiration was done from the iliac crest under local anesthesia maintaining strict asepsis .
aspiration was done using bone marrow biopsy needle and 10 ml syringe prewashed with heparin .
collection was done in cpda ( citrate - phosphate dextrose anticoagulant ) medium using 1 ml of medium for 7 ml of bone marrow .
it was sent to a dedicated stem cell laboratory working as per clinical gmp / gtp standard and having a working area with laminar airflow to class 100 .
bone marrow was centrifuged using histopaque density gradient at 1000 rpm for 10 mins and 102 million mononuclear cells were separated .
these cells were further treated by column separation technique and customized cocktail of cd9 , cd90 , and cd133 antibodies was used for immunomagnetic isolation of endometrial angiogenic stem cells .
gene expression study for cd9 , cd44 , and cd90 using rt - pcr technique was done for differentiated cells .
total 39 million marker - positive endometrial angiogenic cells were supplied in 0.7 ml of pbs ( phosphate buffer saline ) with 2% autologous ( patient 's own ) heat - inactivated serum on the next day for transplant.[616 ] patient was called with partially filled bladder on june 16 , 2009 , second day of her menstrual cycle .
curettage was done under anesthesia . with patient in lithotomy position , sim 's speculum in place ,
anterior retractor was used to retract the anterior vaginal wall , and volsellum was used to hold the anterior lip of cervix .
france ) attached with 1-ml syringe , filled with 0.7-ml stem cell suspension , was advanced through cervix upto the fundal end of the endometrium under transabdominal ultrasound guidance .
when the tip of the catheter was 0.5 cm below the fundus , piston was slowly advanced to allow slow steady flow of cell suspension in the uterine cavity . after instilling 0.3 ml of stem cell suspension at the fundus , injection was continued when cannula was gradually withdrawn out , till the tip reached mid cavity of the uterus .
it was further very gently and slowly withdrawn out of the internal os and then external os , maintaining continuous pressure on the piston to prevent any back flow .
speculum and volsellum were removed , and patient was shifted when she recovered from anesthesia .
she was given oestradiol valerate 6 mg daily , starting on the same day for 25 days .
ultrasound was done on 14 day and 19 day of the cycle , which showed endometrial thickness of 5.0 and 5.2 mm , respectively , and color doppler showed spiral vessels reaching subendometrial zone .
ultrasound scans done at midcycle showed improvement in endometrial thickness , morphology , and vascularity [ figure 4 ] .
well - developed endometrium with low - resistance vascularity reaching zone 4 on november 2 , 2009 , endometrial thickness at ultrasound was 6.9 mm , with vascularity reaching intraendometrial region .
there were dominant follicles in either ovary , which excludes the possibility of any endogenous luteinizing hormone surge . on november 6 , 2009 ,
three 4 - 6 cell grade i donor oocyte ivf embryos were transferred . at this time , her endometrium was multilayered , with thickness of 7.1 mm and intraendometrial vascularity .
she was given progesterone vaginal gel ( crinone 8% , manufactured by fleet laboratories , uk , marketed by merck serono ) twice a day after et , as luteal support and ethinyl oestradiol was continued in a dose of 6 mg daily along with aspirin 75 mg daily .
once -hcg was positive , the dose of oestradiol valerate was increased to 8 mg daily .
progesterone vaginal gel 8% was continued twice a day along with aspirin 75 mg daily .
a single gestational sac of 12 mm , yolk sac of 2.9 mm , embryonic pole of 2.4 mm , with m - mode showing embryonic heart rate of 112/mt were seen at ultrasound on november 30 , 2009 .
follow - up scan was done at 8 weeks of pregnancy which showed a healthy fetus [ figures 57 ] .
gestational sac , yolk sac , and embryonic pole after embryo transfer and positive -hcg test m - mode of cardiac activity of embryo 3d picture of 8 weeks scan
this was a case of infertility with severe asherman 's syndrome and bilateral cornual tubal block with low ovarian reserve . anti - mullerian hormone , which is now considered to be the most reliable marker for ovarian reserve , was not routinely used at that time ( 2007 ) and was not easily available locally , and therefore was not done .
low ovarian reserve with blocked fallopian tubes had left her with an option of oocyte donation .
placement of iucd after surgery and cyclical hormonal therapy in association with low - dose aspirin or nitroglycerine is an established protocol for development of functional endometrium .
placing iucd after curettage , followed by cyclical oestrogen progesterone therapy with aspirin , could not improve her endometrium .
stem cells derived from tissues such as bone marrow , cord blood , adipose tissue , or the amniotic fluid have demonstrated regenerative potential in a variety of diseases and degenerative disorders . therefore , we tried to regenerate the endometrium with adult autologous stem cells after curettage , which was further supported with cyclical estrogen , progesterone , and aspirin for improving vascularization .
bone marrow aspiration is fairly safe procedure with the risk of bleeding or infection , which are extremely rare when done meticulously in the hands of the expert .
currettage was done to evoke injury - induced inflammatory reaction and hyperemia as homing induction , which in turn would enhance the response of endometrium to cyclical hormones .
we would like to qoute a study that has shown regeneration of injured endometrium using adult bone marrow cells .
donor - derived bone marrow cells have been identified in human uterine endometrium. recent evidence has implicated bone marrow - derived cells as possible endometrial progenitors .
it is unknown whether these cells originate from bone marrow mesenchymal stem cells or , alternatively , are circulating endometrial cells originally derived from the endometrium and harbored in bone marrow .
these cells , regardless of their origin , may serve as a source of reparative cells for the reproductive tract .
these data show the potential for stem cells to have a role in the regeneration or repair of this tissue after injury .
significant engraftment of endometrium by bone marrow is likely to occur after endometrial injury or inflammatory insult .
additionally , the proliferation and development of endometrium are entirely regulated by hormonal stimuli . ovarian estrogen and progesterone drive endometrial growth and apoptosis . in the case described in this study ,
we tried to regenerate the endometrium by endometrial angiogenic stem cells isolated from autologous adult stem cells and transplanting them in the endometrium immediately after curettage .
this was based on a study that describes that mononuclear cells collected from the menstrual blood contains a subpopulation of adherent cells and retains expression of the markers cd9 , cd29 , cd41a , cd44 , cd59 , cd73 , cd90 , and cd105 ; the markers used were cd9 , cd44 , and cd90 to isolate the desired cells .
there is a minimal risk of developed cells presenting certain other markers during the process , but immunomagnetic isolation with specific marker antibodies reduces this possibility .
this experimental therapy may be tried on larger scale when the basal layer of endometrium is also damaged by surgical insult .
the risk for malignancies after the use of adult autologous stem cells may be a concern in view of several reports , but we would like to draw attention to the fact that most of these reports discuss the cases where adult autologous stem cells were used to treat malignancies .
the total cost of the therapy in an indian set up comes to approximately rs .
50 000 ( rupees fifty thousand ) , excluding the expense of ivf - et .
moreover , it has an emotional and social advantage that the patient can bear her own child as against surrogacy .
to the best of our knowledge , no case of asherman 's syndrome conceived after endometrial regeneration with adult autologous stem cells after failure of all other conventional modes of treatment has been reported in literature .
this therapy can be used as an alternative to surrogacy in females with severe asherman 's syndrome , though larger trials may be needed to establish this as proved line of treatment .

Answer:
in a woman with severe asherman 's syndrome , curettage followed by placement of intrauterine contraceptive device ( iucd ) ( iucd with cyclical hormonal therapy ) was tried for 6 months , for development of the endometrium .
 when this failed , autologous stem cells were tried as an alternative therapy . from adult autologous stem cells isolated from patient 's own bone marrow
 , endometrial angiogenic stem cells were separated using immunomagnetic isolation .
 these cells were placed in the endometrial cavity under ultrasound guidance after curettage .
 patient was then given cyclical hormonal therapy .
 endometrium was assessed intermittently on ultrasound . on development of endometrium with a thickness of 8 mm and good vascularity , in vitro
 fertilization and embryo transfer was done .
 this resulted in positive biochemical pregnancy followed by confirmation of gestational sac , yolk sac , and embryonic pole with cardiac activity on ultrasound .
 endometrial angiogenic stem cells isolated from autologous adult stem cells could regenerate injured endometrium not responding to conventional treatment for asherman 's syndrome .


Question:
You will be shown the title of a chemistry paper, together with sections excerpted from the body of the paper. The paper sections may include HTML tags like `<p>` and `</p>`; please ignore these. Your task is to write an abstract for the paper. Your response should include the abstract and no other text.

Title:
Synthesis of Stereodefined 1,1-Diborylalkenes via Copper-Catalyzed Diboration of Terminal Alkynes

Paper sections:

Alkenyl boronic acids and their derivatives are non-toxic, shelf-stable organometallic compounds that react with high fidelity in a range of C-C and C-heteroatom couplings, making them useful reagents in organic synthesis. 1 1,1-Diborylalkenes are an emerging subclass that offer exciting potential for accessing multisubstituted olefins in a stereocontrolled manner through sequential reaction at each of the two C-B bonds. 2 To this end, many approaches to synthesize 1,1-diboryl alkenes bearing two -Bpin groups (Bpin = pinacolatoboryl) have been developed from alkene 2c,3 and alkyne starting materials. 4 When such compounds are then employed in cross-coupling, the inherently similar reactivity of the two C-Bpin bonds makes it challenging to achieve high selectivity for a mono-functionalized product. Indeed, successful mono-selectivity at the less hindered position has only been demonstrated when the 1,1-diborylalkene contains an aryl group at the 2-position and when an aryl iodide is employed as the electrophile (Scheme 1 A). 2c,4b We reasoned that the scope of substrates and coupling partners could be expanded if the two boron centers were differentially protected with one -(pin) (pin = pinacolate) and one -(dan) (dan = 1,8-diaminonaphthalenyl) group (Scheme 1 A). The Bdan group is well known to possess diminished Lewis acidity, and to be generally inactive toward transmetalation, a key step of cross-coupling. 5 This so-called protected boron moiety can be reactivated by either deprotection under acidic condition, 5 or interaction with KOtBu or Ba(OH)2. 6 The sequential masking/unmasking strategy enabled by the Bdan group has been successfully applied to iterative cross-coupling, providing efficient and concise approaches to functional organic molecules including complex oligorenes, 5a-c,6c and optoelectronic materials. 5d Moreover, these isomerically pure 1,1-diborylalkenes represent a promising class of prochiral substrates to generate enantioenriched 1,1-diborylalkanes, 7 that are valuable versatile building blocks to access enantioenriched functionalized alkanes. 8

In view of the unique synthetic value of differentially protected 1,1-diborylalkenes, practical synthetic methods to access such complexes in a stereodefined manner are desirable. However, few methods are currently available. In 2017, Chirik and colleagues described a Co-catalyzed 1,1-diboration of aliphatic alkynes to synthesize (Z)-1,1-diborylakenes with use of the mixed diboron reagent pinB-Bdan (Scheme 1 B). 4b Later, Marder reported a base-catalyzed stereoselective diboration of alkynyl esters and amides with pinB-Bdan (Scheme 1 C). 9 Both methods, though highly enabling in their own right, have limited substrate scope and only provide access to the Z-configured products. Driven by our interest in developing new metal-catalyzed alkyne difunctionalization methods, we recently reported a CuH-catalyzed cascade process to access enantioenriched α-aminoboron compounds via sequential hydroboration and hydroamination of terminal alkynes. 10 Here we report an exclusively E-selective Cu-catalyzed three-component reaction to produce 1,1-diborylakenes through a tandem sequence comprised of dehydrogenative C(sp)-H borylation with HBdan and hydroboration of the resulting alkynylBdan intermediate with HBpin (Scheme 1 D).

Our investigation commenced by examining reaction conditions using phenylacetylene (1a) as pilot substrate, with HBdan and HBpin as coupling partners. After extensive optimization, we identified an effective protocol in which HBdan is first mixed with 1a in the presence of 5 mol% Cu(OAc)2 and 5 mol% (Ra)-DTBM-SEGPHOS in THF for 15 min. After this period HBpin is added, and the reaction is allowed to stir for an additional 16 h at room temperature, at which point the desired product 2a is isolated in 69% yield. (Table 1, entry 1) The timing of HBpin addition was found to be important. The yield of 2a decreased when HBpin added earlier, with larger amount of side products observed (Table 1, entries 2-3).

underdeveloped

Another key finding from these studies was that acetate counteranion and (Ra)-DTBM-SEGPHOS ligand were both required (Table 1, entries 4-12). CuOAc was slightly less effective than Cu(OAc)2 (Table 1, entry 4), while other copper sources such as CuBr and CuCl, together with NaOtBu, showed no catalytic activity. In terms of other ligands tested, (Ra)-DM-SEGPHOS gave slightly lower yield of 2a than (Ra)-DTBM-SEGPHOS (Table 1, entry 12). Other phosphine ligands unfortunately led to either low yield or no reaction. There was no reaction in the absence of a ligand (Table 1, entry 13). The structure and (E)-stereochemical configuration of 2a were unambiguously assigned by X-ray crystallography ( Standard reaction conditions: 1a (0.10 mmol), HBdan (0.11 mmol), HBpin (0.12 mmol), Cu(OAc)2 (5 mol%), and (Ra)-DTBM-SEGPHOS (5 mol%) in THF (0.25 mL). b 1 H NMR yield using CH2Br2 as internal standard. c 10% of PhCHCH(Bpin) was also observed. d Together with NaOtBu (10%). e 9% of PhCHC(Bpin)2 was observed.

Next, we evaluated the scope and functional group compatibility of this stereoselective process (Table 2). The reactions with aryl-substituted alkynes were found sensitive to both electronic and steric effects. Aryl acetylenes with electron-donating groups normally performed better than those with electron-withdrawing groups. For example, p-MeO-substituted phenylacetylene gave product 2c in 70% yield, while p-CF3substituted phenylacetylene gave product 2f in 47% yield. Diboration of para-substituted phenylacetylenes generally occurred smoothly while meta-and ortho-substituted phenylacetylenes gave relatively low yield. A range of functional groups, such as halides (2e, 2k, 2l, 2m), an ester (2g), ethers (2c, 2i) and amines (2d, 2j), were well tolerated. 2-Ethynylnaphthalene and 3-ethynylthiophene underwent diboration as well to give corresponding 1,1-diborylalkenes (2h, 2n).

1,1-Diboration was similarly effective with aliphatic alkynes, furnishing the corresponding E-configured products as well. The structure of 1,1diborylalkene 2o was confirmed by X-ray crystallography (Table 2, bottom left). Remarkably, 1-ethynylcyclohexene underwent 1,1-diboration to furnish product 2s with C=C double bond intact. Functional groups like carbonate (2p), ether (2q) and silyl ether (2t) were tolerated with products isolated in useful yields. Conditions: 0.10 mmol scale, THF (0.25 mL). Percentages correspond to isolated yields.

Interestingly, when terminal alkynes 1 were reacted with 2.2 equiv HBdan in the absence of HBpin, 1,1-homodiboration proceeded smoothly, furnishing 1,1-diborylalkenes 4 bearing two -Bdan groups in excellent yields (eq. 1).

To illustrate the practical utility of this procedure, we performed stepwise Suzuki-Miyaura cross-couplings of 1,1-diborylalkenes (Scheme 2). The selective monoarylation of 2a worked well using 4-iodotoluene as coupling partner under standard cross-coupling conditions, giving 92% 5a after 12 h at 30 °C. Notably, the reaction with 4-bromotoluene also proceeded, albeit at a higher temperature of 80 °C, giving product 5a in 85% yield with no diarylation product detected. Next, the Bdan group of 5a was deprotected, and the resulting boronic acid was carried forward without purification in a second cross-coupling reaction with 4iodoanisole to produce triarylated alkene 6a as a single stereoisomer.

Scheme 2.

Stepwise Suzuki-Miyaura coupling reactions of 2a.

Having established the scope and utility of the (E)-selective alkyne 1,1diboration method, we shifted our attention to investigating the reaction mechanism. Subjecting sterically bulky mesitylacetylene to the standard reaction conditions did not lead to formation of the typical 1,1-diboryalted product; instead, alkynylBdan 3u was isolated in 55% yield (eq. 2). This result suggests that alkynylBdan is the product from first step of the tandem process and that the second hydroboration step is sensitive to steric hindrance. Consistent with this notion, the reaction between 2a and HBdan before addition of HBpin was monitored by 1 H NMR spectroscopy (eq. 3), and 16% alkynylBdan 3a and H2 were both observed after 30 min (SI, Figure S1). To further support our hypothesis, the proposed intermediate 3a was independently synthesized and submitted to the reaction with HBpin under the standard conditions. Hydroboration of 3a proceeded smoothly to furnish 2a in 60% yield (eq. 4).

equiv

Based on our experimental observations and previous reports, 11-13 a Cucatalyzed tandem process comprised of dehydrogenative borylation of terminal alkynes and following hydroboration is proposed (Scheme 3).

[LCuOAc] a1, generated by reduction of Cu(OAc)2 in the presence of phosphine, 14 reacts with terminal alkynes to give the alkynylcopper intermediate a2 and HOAc. 13b,15 Following σ-bond metathesis between a2 and HBdan gives alkynylBdan 3 and [LCuH] a3. 11,16 syn-Insertion of a3 to intermediate 3 generates alkenyl copper species a4, 12,13,17 which then undergoes σ-bond metathesis with HBpin to furnish the (E)-1,1-diborylalkenes and regenerate [LCuH] a3.

Under the optimal conditions, prior to addition of HBpin, the right cycle alone proceeds through several turnovers to build up 3a, and upon addition of HBpin the left cycle turns on. This strategy limits the formation of side products caused by the high reactivity of HBpin. In the 1,1-homodiboration system with HBdan only, both cycles presumably proceed in parallel. 18

In conclusion, we have reported the first (E)-selective synthesis of 1,1diborylalkenes bearing one -Bpin group and one -Bdan group from terminal alkynes via a Cu-catalyzed tandem process. A wide range of aryland alkyl-substituted alkynes underwent this transformation, giving the corresponding 1,1-diborylalkenes with broad functional group tolerance. We have also demonstrated that differentially protected 1,1-diborylalkenes are useful synthetic intermediates for the construction of multi-substituted alkenes with stereocontrol. Further applications of 1,1-diborylalkenes for the synthesis of more complex compounds are being pursued in our laboratory.

Scheme 3. Proposed mechanism.

Supporting Information

The Supporting Information is available free of charge at DOI: [filled later]. Detailed experimental procedures and compound characterization (PDF) Crystallographic data for 2a (CIF) Crystallographic data for 2o (CIF)

AUTHOR INFORMATION

Corresponding Author *E-mail: keary@scripps.edu

ORCiD

Yang Gao: 0000-0001-9270-6251 Keary M. Engle: 0000-0003-2767-6556

Notes

The authors declare no competing financial interests.

Answer: ration of terminal alkynes is described. The tandem process involves sequential dehydrogenative borylation of the alkyne substrate with HBdan (HBdan = 1,8-diaminonaphthalatoborane), followed by hydroboration with HBpin (HBpin = pinacolborane). This method proceeds efficiently under mild conditions, furnishing 1,1-diborylalkenes with excellent stereoselectivity and broad functional-group tolerance. Taking advantage of the different reactivities of the two boryl moieties, the products can then be employed in stepwise cross-couplings with aryl halides for the stereocontrolled construction of trisubstituted alkenes.


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
snoring is not a benign symptom . it is associated with an increased risk of hypertension , cardiac arrhythmias , and mortality .
snoring is defined as a sound produced when an individual breaths during sleep due to the turbulence of air passing through the partially obstructed airway .
it is considered as one of the most common clinical symptoms of obstructive sleep apnea ( osa ) .
snoring may result in excessive daytime sleepiness , loss of concentration , and psychological disturbances that may eventually cause deterioration of the patient life quality unless treated .
this wide range is due to the differences in the populations studied , study design , investigations performed , ethnic group , age , and sex of the subjects .
snoring is potentially related to the increase in the body mass index ( bmi ) , cigarette consumption , ethnic differences , infections , and hypertension .
nocturnal polysomnography is considered the best tool to investigate whether snoring is a health risk .
however , it is not widely available and expensive to be used as a screening tool , as it is mostly available only in specialized sleep clinics .
therefore , the use of questionnaires like berlin questionnaire become a simple and effective method of screening for snoring and risk of osa .
in addition , many craniofacial features and malocclusions were reported to be associated with snoring .
for example ; narrow airway at the level of the soft palate and oropharynx , more inferiorly positioned hyoid bone , more protruding maxilla , anterior - posterior discrepancy of maxilla and mandible , class ii malocclusion , increase in over - jet , reduced overbite , narrower upper , and shorter lower dental arch and crowding in the mandibular arch .
according to literature , snoring was associated with osa , and the characteristics were complicated with other dentofacial risk features such as facial profile , malocclusion classification , and dental arch morphology .
for instance , stellzig - eisenhauer and meyer - marcotty ( 2010 ) reported a significant difference between patients with retrognathism and pragmatism in respect to the transverse dimension of the nasopharynx .
however , de freitas et al . , found no correlation between obstructions of the upper airway and the frequency of malocclusions .
this reflects the discrepancy between the influence of the facial profile , malocclusion classification , and dental arch morphology on airway measurements .
therefore , the aim of this study was to test the null hypothesis that there is no morphological difference in facial profile , malocclusion class , and dental arch morphology in adult yemenis male with and without snoring .
rejection of the null hypothesis might improve our understanding of the influence of snoring on the surrounding dentofacial structures .
after the study was approved at the institutional level and informed consent was obtained , a cross - sectional study was carried out among male students and employees at the university of science and technology . for the prevalence study ,
the sample size was calculated using power and sample size software ( 5.2 mb version 2.1.31 . ) which indicated 840 subjects is required for this study . when the participants agreed to participate in the study
, a consent form was given along with a set of the sleep behavior questionnaire ( berlin questionnaire ) .
the inclusion criteria were : age 18 and above , healthy individuals without any diseases or congenital abnormalities and the presence of at least six teeth in each maxillary and mandibular arch .
each selected subject undergone clinical examination , upper and lower arch impression , and bmi calculation .
totally , 150 participants ( 75 snorers : 9 employees , 66 students ) and ( 75 nonsnorers : 8 employees , 67 students ) were able to complete their required records .
bmi was calculated from the patient 's height and weight in standard units ( kg / m ) , and neck circumference ( nc ) was measured at the level of the thyroid cartilage .
the facial profile was assessed by classifying the facial profile into convex , concave , and straight .
assessment of arch morphology and palatal morphology were carried out as following : arches were classified as constricted and nonconstricted . the dental arch constriction was defined as the presence of two or more maxillary posterior teeth in edge to edge cuspal relationship with their antagonists , or in a frank cross bite .
the palatal morphology divided into u - shaped ( normal ) and v - shaped ( constricted ) .
maxillary constriction was defined by the presence of all the following features : a narrow and high palatal vault ; corresponding narrow arch form and unilateral or bilateral buccal tilting of the maxillary alveolar arches with posterior teeth in crossbite or edge to edge relationship with the lower teeth .
assessment of dental cast parameters were completed by taken dental impression and fabricating a set of upper and lower models .
alginate impression material ( zhermack , germany ) mixed according to the manufacturer 's instructions .
the following measurements were recorded using digital calipers : inter - canine distance ; inter - premolar distance ; intermolar distance ; arch length ; palatal cast depth .
out of 840 questionnaires distributed , 700 were returned ( 77 employees and 623 students ) ; the response rate was 80% .
nine were employees ( 11.7% ) , and 105 were students ( 16.9% ) . totally ,
150 participants ( 75 snorers ) and 75 nonsnorers were able to complete their required records and , therefore , were included in the comparison study .
table 1 shows the demographic profile of 150 subjects who were males with mean age of 24  4 years , mean height of 167  6 cm , mean weight of 63  10 kg , mean bmi of 22.5  3 kg / m , and mean nc 36  2.6 cm .
clinical observation of snorers and non - snorers extra - oral variables accordingly , the mean neck size was found to be significantly greater for the snorer group ( 36.6  2.5 ) than nonsnorer group [ 35.4  2.6 ; p < 0.007 ; table 1 ] .
clinical examination shows that the most frequent finding among snorer groups when compared with the nonsnorer group were straight profiles ( 52.0% ) , class i malocclusion ( 74.7% ) , and v palatal shape ( 16.0% ) , respectively [ table 2 ] .
the chi - square test revealed a significant difference among the v - shape palatal morphology ( p < 0.034 ) , but no significance was found in terms of the facial profiles ; malocclusion class or arch morphology .
in addition , the upper arch length was significantly shorter ( 35.6  2.5 ) in the snorer subjects than the nonsnorer group ( 36.4  2.5 ; p < 0.038 ) , and the inter- first upper premolar distance was significantly narrower ( 39.6  2.6 ) in the snorer subjects than in the nonsnoring group [ 40.8  2.9 ; p < 0.013 ; table 3 ] . orthodontic observation of facial profile , malocclusion class , arch morphology and palatal shape orthodontic observation of dental cast measurements ( meansd ) in snorers and non - snorers
the present study was carried out to determine the prevalence of snoring among male adult at university population setting and to compare the craniofacial features of an adult with and without snoring using clinical examination .
in addition , the clinical examination showed that the snoring in our adult university population manifested a significantly different craniofacial feature , such as a v - shaped palate ; higher nc ; lower upper arch length ; and a decrease in the inter- first upper premolar distance . based on our prevalence of snoring result , it seems that the prevalence of snoring in our sample is slightly higher from the average of snoring prevalence quoted earlier but lesser compared with the other studies in student population .
table 4 summarized previous studies of snoring among the student population . comparing our result to malaysian medical students ,
our result showed a higher percentage of snoring , which might be due to a mixture of students and employees in our sample ; different age ; and bmi and diverse definition of snoring .
concluded that snoring was prevalent in student population , and male gender showed a trend as an independent predictor for snoring , which is similar to our result .
summery of snoring among the student population ( from most to least severe ) when we compared our result with the general adult population findings , our result is slightly lower than the prevalence of snoring reported by middle - eastern studies ( 52.3% saudi and 28.7% jordanian bahammam et al . and khassawneh et al . ,
however , in asian adults , it was found that the prevalence of snoring is higher than the western population study .
nevertheless , it should be understood that the prevalence of snoring does not necessarily indicate the development of obstructive complications but these findings do highlight the need for awareness about possible complications .
the results of this current study , indicate the nc is significantly greater for the snoring group than for the nonsnorer group .
this finding supports the view that nc is one of the significant risk factors for yemeni snorer , which is in good agreement with findings obtained in the chinese and japanese populations . increased nc even in the absence of obesity in our subjects ,
may draw our attention on the importance of the fat tissue around the neck in nonobese individuals . furthermore , snoring and greater nc were also considered as useful clinical predictors of osa .
clinical examination findings indicate that the most frequent finding among snorer groups were straight profiles ( 52.0% ) , class i malocclusion ( 74.7% ) , and v palatal shape ( 16.0% ) , respectively .
even though , there is no relationship between upper airway obstruction and the type of malocclusion were found but it has been reported that the upper pharyngeal width in the subjects with class i and class ii malocclusions with the vertical growth patterns were significantly narrower than in the normal growth pattern group .
therefore , this makes the orthodontist more alert to enquire about snoring even in class i malocclusion and straight profile patients especially with vertical growth patterns . on the other hand
, it has been reported that convex profiles ( 71.7% ) , class ii malocclusion ( 51.7% ) , and v palatal shape ( 53.3% ) were frequent features in an asian osa sample .
this in contrast to our current study , and this could be related to the difference between the osa as a general term while the snoring is one of the osa symptoms and to the differences in the cranial base morphology between asians and caucasian . using dental examination
, we found statistically significant difference between yemeni snorers and nonsnorer in a v - shape palatal arch ; the arch length and the inter- first premolar distance . in view of the fact that the roof of the mouth is also the floor of the nose , a narrow arch can infringe on the nasal cavity space
therefore , maxillary constriction , in addition to his responsibility as one of the important factors for determining nasal airway properties , it can also contribute to lateral narrowing of the upper oral cavity and a low tongue posture which consequently narrow the retroglossal region .
this may provide a reasonable explanation for the narrowing of the posterior airway space seen in osa patients . the v palatal shape was also included as one predictive morphometric model for osa , and the model illustrates the potential value of physical and dental examination .
for instance , there is a possibility of under diagnosis of snoring when a standard full night polysomnography test is not administered .
however , berlin questionnaire can still be considered as an effective and inexpensive way for screening snoring .
another limitation of this study is the fact that females were not included . for cultural factors
, this study suggests that snoring among our university population is associated with increased nc ; v - shape palatal morphology ; the short upper arch length ; and narrow inter- first upper premolar distance .
clinically , increased nc even in the absence of obesity may draw our attention to the importance of the fat tissue around the neck in nonobese individuals .
in addition , the orthodontist and other health care should be more alert to enquire about snoring , take the complaint of snoring seriously , and perform a thorough clinical and orthodontic evaluation even in class i malocclusion and straight profile patient especially college - aged male adult with vertical growth patterns .
furthermore , on the basis of clinical and orthodontic observation that have been recognized in this study , we believe that those observation features could be used to improve our understanding of the influence of snoring on the surrounding dentofacial structures of the adult university population and may provide valuable screening information in the identification of patients with undiagnosed osa .
further studies are needed to find other clinical and orthodontic features in a diverse university population with different ethnic and sex trends in regards to snoring patterns .
is associated with v - shape palatal morphology , increased nc , and decrease in the upper arch length and inter- first upper premolar distance .

Answer:
objectives : the objectives of this study were to determine the prevalence of snoring in an adult male university population , and to test the null hypothesis that there is no difference in facial profile shape , malocclusion type , or palatal morphology among snorer and nonsnorer.materials and methods : berlin questionnaire was given to 840 students and employees aged 1845 years ( 24  40 ) . both snorers and nonsnorers were assessed for the facial profile type , malocclusion type , and palatal morphology .
 chi - square and student 's t - test were used to compare the difference between the two groups.results:the prevalence of snoring was 16.28% .
 the most frequent findings among snorer were straight profiles ( 52.0% ) , class i malocclusion ( 74.7% ) , and v palatal shape ( 16.0% ) , respectively .
 the chi - square test revealed a significant difference in terms of v - shaped palatal morphology ( p < 0.05 ) ; higher neck circumference ( nc ) ( p < 0.007 ) ; upper arch length was significantly shorter ( p < 0.038 ) ; and the inter- first upper premolar distance was significantly narrower ( p < 0.013).conclusion : the null hypothesis is rejected .
 snoring in our university population is associated with v - shape palatal morphology , increased nc and decrease in the upper arch length , and inter- first upper premolar distance .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
to ensure successful pain relief , in - depth knowledge of local anesthetic solutions and appropriate application of local anesthetic techniques is mandatory .
the inferior alveolar nerve block is the most frequently used nerve block technique for anesthetizing mandibular teeth during endodontic procedures . in case of symptomatic irreversible pulpitis
the success rate of mandibular anesthesia with the inferior alveolar nerve block has been reported to vary from 38 - 85% .
previous studies have shown success rates of only 19 - 56% for inferior alveolar nerve blocks in patients with irreversible pulpitis .
it is evident from these studies that severely painful inflamed tooth is often difficult to manage conventionally and local anesthetic failure is a common occurrence .
these include periodontal ligament injection , intrapulpal injection , intraosseous injection , and intraseptal injection .
supplemental injections are essential in patients with irreversible pulpitis as the local anesthetic injections had an eight - fold higher failure rate compared to normal patients .
needleless device uses pressure to force the anesthetic solution safely into oral tissues . in needleless jet injection ,
the anesthetic solution is immediately taken up by the myelin sheath of the nerve with an onset of action of approximately 1 ms .
the x - tip intraosseous injection allows deposition of a local anesthetic solution directly into the cancellous bone adjacent to the tooth to be anesthetized .
success of these supplemental intraosseous injections in achieving pulpal anesthesia in patients with irreversible pulpitis has been reported to be 82 - 98% .
the intraosseous systems available commercially in the market include the stabident system ( fairfax dental inc . ,
miami ) , x - tip system ( x - tip technologies , dentsply , maillefer ) , intraflow ( intra vantage , plymouth , mn ) , and the quicksleeper ( dht , cholet , france ) .
clinical trial studies have been published using stabident , x - tip sytem , intra flow , and the quicksleeper system .
the x - tip anesthesia delivery system consists of a special hollow needle that serves as the drill and guide - sleeve component .
the drill leads the guide sleeve through the cortical plate after which it is separated and withdrawn .
the guide sleeve remains embedded in the bone and the anesthetic solution is delivered with the aid of a 27-gauge needle .
there has been a continual search for safer and more profound local anesthetic compounds for attaining adequate pulpal anesthesia .
articaine , classified as an amide anesthetic , has increased liposolubility and potency because of the presence of a thiophene ring .
greater diffusion of articaine anesthetic solution to the teeth can be attributed to increased liposolubility and smaller size of thiophene ring of articaine in contrast to benzene ring of lignocaine . according to some authors ,
ability of articaine to diffuse into the bone can produce pulpal anesthesia in mandibular teeth even after infiltration anesthesia .
clinical studies comparing the success rate of 4% articaine with that of 2% lignocaine have shown that 4% articaine was superior to 2% lignocaine as a general - purpose anesthetic .
the purpose of the study was to evaluate the anesthetic efficacy of x - tip intraosseous injection in patients with symptomatic irreversible pulpitis in mandibular posterior teeth , using 4% articaine with 1:100,000 adrenaline as local anesthetic when the conventional inferior alveolar nerve block proved ineffective .
the purpose of the study was to evaluate the anesthetic efficacy of x - tip intraosseous injection in patients with symptomatic irreversible pulpitis in mandibular posterior teeth , using 4% articaine with 1:100,000 adrenaline as local anesthetic when the conventional inferior alveolar nerve block proved ineffective .
thirty patients , 15 males and 15 females 15 - 53 years of age with a diagnosis of symptomatic irreversible pulpitis of mandibular posterior teeth were included in this study .
approval for the study was obtained from institutional ethical committee and written informed consent was acquired from each patient .
the diagnosis of irreversible pulpitis was confirmed by a chief complaint of spontaneous pain or pain at night , together with cold test and electric pulp testing showing an elevated and lingering pain response .
vitality of these teeth was first tested with cold pulp tester , dichlorodifluoromethane ( endo - frost , roeko , langenau , germany ) followed by electric pulp tester ( digitest pulp tester ) . in all 30 patients selected , control teeth showed normal response and the inflamed teeth showed an elevated and prolonged pain response to these tests .
inferior alveolar nerve block injection was administered using 1.7 ml of 4% articaine with 1:100,000 adrenaline ( septanest with adrenaline 1:100,000 , septodont , france ) with conventional long buccal injection . before commencing access preparation
, it was ensured that the control teeth did not respond to the maximum output of the electric pulp tester and the cold test .
the patients were instructed to rate any discomfort during access using a heft - parker visual analogue scale ( vas ) [ figure 1 ] . the vas scale consists of four categories .
mild pain was defined as greater than 0 mm and less than or equal to 54 mm .
supplemental intraosseous x - tip injection was administered in patients who had moderate or severe pain ( vas rating greater than 54 mm ) on access into dentin , when entering the pulp chamber or with initial file insertion .
heft - parker vas pain scale used for pain assessment the intraosseous injection with the x - tip system ( dentsply maillefer , usa ) was administered in the following manner : the perforation site was selected according to manufacturer 's instructions , 2 - 4 mm apical to alveolar crestal bone level in the attached gingiva , at a site distal or mesial to the operating tooth .
after determination of the perforation site , the perforator attached in micromotor handpiece was pushed through the attached gingiva until the x - tip contacted bone . after placing the drill at a 90 angle to the bone , the slow - speed air motor handpiece was activated and drilled at 90 to the bone . in 2 - 4 seconds , the drill perforated the cortical bone into the cancellous bone .
the handpiece was always activated while the perforator was within the bone to prevent breakage that might occur if the perforator was allowed to stop rotating .
after perforation , the drill was withdrawn from the guide sleeve , leaving the guide sleeve in place .
the 27-gauge ultrashort x - tip needle was inserted into the guide sleeve to its hub , and 1.7 ml of 4% articaine with 1:100,000 adrenaline ( septanest with adrenaline 1:100,000 , septodont , france ) was delivered over a 1-minute time period .
the success of the supplemental x - tip technique is defined as the ability to access the pulp chamber , place initial files , and instrument the tooth without pain ( vas score of zero ) or mild pain ( vas rating less than or equal to 54 mm ) .
if the patient had moderate to severe pain ( vas rating greater than 54 mm ) during access or initial instrumentation , the x - tip technique was considered as a failure and an intrapulpal injection was administered .
out of the 30 patients who participated in the study , 25 patients experienced no pain or mild pain and were counted as success .
five patients who experienced moderate to severe pain during access or initial instrumentation after intraosseous injections were considered a failure .
the various factors associated with anesthetic failure for conventional ian block include accessory innervations , accuracy of needle placement , anesthetic solution migration along the path of least resistance , tetrodotoxin - resistant class of sodium channels , which have been shown to be resistant to the action of local anesthetics , anxiety , psychological factors , and altered resting potentials and decreased excitability thresholds of nerves arising from inflamed tissue . owing to these myriad limiting factors , supplemental injections become necessary in cases when inferior alveolar nerve block is not effective in providing satisfactory anesthesia . in needle - phobic patients ,
the time of onset of action for pressure anesthesia was less when compared to classic needle infiltration but the total duration of anesthesia was more for needle infiltration anesthesia . it can be used for restorative procedures of short duration and direct pulp injections . in this study , the anesthetic success using x - tip intraosseous injection was 83.33% .
the results of this study shows that supplemental x - tip intraosseous injection helps in achieving successful pulpal anesthesia in patients with symptomatic irreversible pulpitis .
none of the x - tip perforators broke , and the onset of anesthesia was immediate .
the thickness of the cortical plate of posterior mandibular region condemns the use of infiltration injections .
the intraosseous injection overcomes this problem by allowing direct access to the cancellous bone via perforation of the cortical bone . in this study ,
this fact is critical , as higher the lipid solubility , the higher is the potency and better will be the diffusion through the medium into which it is injected , and therefore , the greater is its ability to cross the lipid membranes of the epineuria
this molecular configuration is subject to rapid hydrolysis by plasma cholinesterases after it is absorbed into the systemic circulation .
only the remaining 5 - 10% is subject to the slower , traditional hepatic metabolism .
the allergen paraminobenzoic acid ( paba ) , a frequent metabolite of ester metabolism , is not a by - product of the hydrolysis phase of articaine .
within the limitations of this study , we can conclude that when the inferior alveolar nerve block fails to provide profound pulpal anesthesia , the x - tip system using 4% articaine , was successful in achieving pulpal anesthesia in mandibular posterior teeth of patients presenting with irreversible pulpitis .
supplemental intraosseous injection with x - tip using 4% articaine with 1:100,000 adrenaline enabled soothing , swift , and sound anesthesia .

Answer:
introduction : pain management remains the utmost important qualifying criteria in minimizing patient agony and establishing a strong dentist  patient rapport .
 symptomatic irreversible pulpitis is a painful condition necessitating immediate attention and supplemental anesthetic techniques are often resorted to in addition to conventional inferior alveolar nerve block.aim:the purpose of the study was to evaluate the anesthetic efficacy of x - tip intraosseous injection in patients with symptomatic irreversible pulpitis , in mandibular posterior teeth , using 4% articaine with 1:100,000 adrenaline as local anesthetic , when the conventional inferior alveolar nerve block proved ineffective.materials and methods : x - tip system was used to administer 1.7 ml of 4% articaine with 1:100,000 adrenaline in 30 patients diagnosed with irreversible pulpitis of mandibular posterior teeth with moderate to severe pain on endodontic access after administration of an inferior alveolar nerve block.results:the results of the study showed that 25 x - tip injections ( 83.33% ) were successful and 5 x - tip injections ( 16.66% ) were unsuccessful.conclusion:when the inferior alveolar nerve block fails to provide adequate pulpal anesthesia , x - tip system using 4% articaine with 1:100,000 adrenaline was successful in achieving pulpal anesthesia in patients with irreversible pulpitis .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
tetralogy of fallot ( tof ) accounts for approximately 5% to 7% of all cases of congenital heart disease .
complications related to surgical repair of tof are clinically relevant and include pulmonary regurgitation , residual obstruction of the right ventricular ( rv ) outflow tract , rv systolic dysfunction , and arrhythmias . among these ,
residual rv outflow tract obstruction with accompanying pulmonary regurgitation is the most frequently reported sequela after initial surgical correction of tof .
therefore , a systolic murmur that is audible over the base of the heart is frequently interpreted as a residual rv outflow tract lesion . however , this is not always true .
we herein report a rare case of subaortic stenosis in association with a previous tof surgical repair that was not considered to be a differential diagnosis .
discrete subaortic stenosis is generally thought of as a disease of children or young adults ( < 25 years of age ) and is thus rarely reported in subjects older than 25 years , particularly in association with tof .
a 29-year - old woman presented for a routine check - up of surgically corrected congenital heart disease . at 7 years of age , she had undergone surgical repair of tof with excision of the infundibular stenosis and closure of a 10-mm ventricular septal defect .
she had been asymptomatic until her first decade of life , and only a 5-year clinical follow - up had been performed after the operation . approximately 6 months prior to presentation , she began to feel exertional dyspnea that was progressively aggravated . on physical examination , she was alert and well - oriented .
her blood pressure was 100/60 mmhg , pulse 60 beats / min , respiration rate 18/min , and body temperature 36.6. the left ventricular ( lv ) impulse was almost normal in location .
on auscultation , a grade 3 of 6 mid- to late - systolic murmur was audible over the base of the heart and heard clearly on both sides of the sternum .
routine blood examinations , including a complete blood count , chemistry panel , coagulation panel , and c - reactive protein level , were all within normal ranges .
transthoracic and transesophageal echocardiograms both demonstrated severe subaortic stenosis due to a subvalvular membrane , on which a mobile mass - like structure that was suspicious of a vegetation was noted ( fig .
there was a mild degree of tricuspid regurgitation , but no clinically significant obstruction of the rv outflow tract .
the maximum velocity measured across the tricuspid valve was 2.8 m / sec , and thus the maximal pressure gradient was estimated to be 31.4 mmhg using the simplified bernoulli equation . due to the up to 20 mmhg pressure gradient across the pulmonary valve
her rv was not dilated , and its systolic function was good . due to the suspicion of infective endocarditis despite the absence of clinical evidence , blood cultures were performed three times ; however , no pathogen was cultured .
the patient underwent resection of the subaortic membrane and myomectomy of the lv outflow tract along with aortic valve commissurotomy .
the membrane , with the exception of the noncoronary cusp area , was located beneath the aortic annulus ( i.e. , inverted u shape ) .
the mobile mass - like structure described on transesophageal echocardiography was proven to be loose tissue attached to the subaortic membrane .
although subaortic stenosis is the second most - common form of lv outflow tract obstruction , it is predominantly found in children or adolescents [ 4 - 8 ] .
subaortic stenosis is strongly associated with other congenital heart defects ; however , subaortic stenosis in association with tof , especially in women , is extremely rare . according to a medline database review of the last 30 years
furthermore , all were diagnosed in childhood or adolescence ( < 20 years of age ) with two exceptions .
the present case is peculiar in that subaortic stenosis manifested more than 20 years after the initial tof surgical correction .
although we could not definitively say that the subaortic stenosis in the present case was acquired , we consider it an acquired or progressive form given the long interval ( > 20 years ) before echocardiographic confirmation .
thomas and foster   suggested that acquired subaortic stenosis can develop gradually due to hemodynamic disturbances derived from coexisting lesions or after surgical correction .
moreover , the mass - like mobile structure observed on transesophageal echocardiography could be regarded as a degenerative byproduct of flow convergence induced by the subaortic membrane , further supporting the concept of an acquired or progressive form of the disease .
discrete subaortic stenosis is well - known to be linked to important complications , such as bacterial endocarditis and significant aortic regurgitation .
flow turbulence distal to the obstructing subaortic membrane plays a crucial role in progressive damage to the aortic valve with resultant thickening of its leaflets and regurgitation .
the secondary jet lesion also predisposes the patient to bacterial endocarditis . in this context ,
in particular , patients with surgically corrected tof tend to be misinterpreted as having only residual rv outflow obstruction without consideration of the lv outflow tract lesion .
transthoracic and transesophageal echocardiography can assist differentiation of the rv from the lv outflow tract obstruction .
therefore , periodic performance of echocardiography should be kept in mind during follow - up of patients with surgically corrected tof .

Answer:
we herein report a rare case of subaortic stenosis in association with a previous tetralogy of fallot ( tof ) surgical repair , which was not taken into account as a differential diagnosis .
 echocardiography plays a pivotal role in identification of this rare combination .
 therefore , echocardiography should be performed periodically during follow - up of patients with surgically corrected tof .
 given the clinical complications that can result from subaortic stenosis ( i.e. , aortic regurgitation and infective endocarditis ) , early and aggressive management of this rare combination should be performed .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
in our model , each particle consists of a core sphere with four tetrahedrally oriented arms ( see fig .
the central sphere and the arms are modeled as interpenetrating hard spheres with diameter  , with the centre of each arm located a distance l from the centre of the core . on the surface of each arm
the patch is modeled , via a standard kern - frenkel potential , as a square - well type attraction of depth  : two particles are either bound or unbound , with no intermediate energy levels .
the opening angle of the patch is given by cos  = 0.95 , and the maximum interaction range  = 0.251. this choice ensures that each patch can form a bond with only a single other patch .
furthermore , in order to model arm flexibility , each arm can freely rotate around the core sphere within a maximum angle  from its ideal ( tetrahedral ) position .
note that there are no hard - core interactions within a particle : spheres belonging to the same tetramer can overlap .
each mc simulation included translation moves , rotation moves rotating a full tetramer , rotation moves rotating only the core sphere , and rotation moves that rotate a single arm around the core . additionally , we added volume moves for isobaric simulations , and particle insertion and deletion moves for grand - canonical successive umbrella sampling ( sus )   simulations . to detect ll phase separation , we used sus simulations , generating the relative free energy as a function of the density . to calculate the phase diagrams in fig . 4 , and the crystallization lines in figs . 2 and 3
for the liquid phases , we used a high temperature fluid as a reference state , where we obtained the helmholtz free energy f by combining the chemical potential  ( evaluated from a sus simulation ) and the pressure p at the same density  ( taken from an npt mc simulation ) , using :
 ( 1)ffn=p ,
 where n is the number of particles .
we then used thermodynamic integration by integrating the temperature along an isochore :
 ( 2)2f(,t2)=1f(,t1)+12du(,t ) ,
 with u( , t ) the average potential energy per particle ,  = 1/kbt and kb boltzmann s constant .
typically , at sufficiently low temperatures , the energy as a function of temperature takes the form
 ( 3)u=2+cexp(2 ) ,
 where 2 is the ground - state energy ( where each particle has four bonds ) and c is a ( density - dependent ) constant .
this allows for straightforward extrapolation of the free energies to arbitrarily low temperatures after the regime in eq .
this regime is accessible in our simulations for all cases where the fluid does not crystallize at low t ( i.e. cos   0.9 ) . system sizes for the sus simulations
were chosen such that near the ll transition the system contained n  150 particles .
other free - energy calculations were performed with similar or larger n. the investigated crystal structures were diamond and bcc ( corresponding to ice ic and ice vii in water , respectively ) . both are fully bonded structures and as such have the ( same ) lowest possible potential energy . depending on cos  and l , there will be a variety of other fully bonded crystal structures .
however , the structures commensurate with an ideal tetrahedral geometry will always have the highest entropy and hence will be more stable at the densities where they are accessible .
thus , the only crystals which might compete with the ll phase separation are diamond and bcc . at high density ,
i.e. beyond the bcc density , the stable crystalline phases will be controlled by a competition between packing , energy , and entropy , but as these phases will not change the stability of the ll phase transition , they are outside of the scope of this letter .
similarly , we do not expect these crystal phases to affect the phase diagrams in fig .
4 , with the possible exception of the ( dashed ) high - density liquid - bcc lines in panels ( c ) and ( d ) . to determine free energies for the crystal phases , we used an einstein crystal approach , for each t where a phase coexistence was calculated .
subsequently , using npt mc simulations , we employed thermodynamic integration along the density at constant temperature :
 ( 4)f(,t)=f(ref , t)+refd()p2 ,
 where ref is the density where the reference free energy was calculated .
s4 in the si for examples ) . to determine whether spontaneous crystallization occured in our sus simulations , we used a bond - order parameter to find the largest crystalline cluster in the system .
first , we determine the neighbors of each particle using a solid - angle based nearest - neighbor method .
we then calculate for each particle the complex vector ql , the expansion of their environment in terms of spherical harmonics ylm , with l
the order of the symmetry of the crystal , and l  m  l :
 ( 5)qlm(i)=1nb(i)j=1nbylm(r^ij ) .
 here , nb is the number of neighbors of particle i , and r^ij is the normalized vector connecting particle i to particle j. for the purpose of finding crystalline clusters , two particles are considered bonded when their environments are sufficiently similar . to determine this , we calculate :
 ( 6)dl(i , j)=re(ql(i)ql(j)ql(i)ql(j) ) .
 to detect bcc clusters , we choose l = 6 , consider two particles bonded if dl(i , j ) > 0.6 , and label any particle that has at least 5 bonds as a crystalline particle . for diamond , two particles
are considered bonded if either dl(i , j ) < 0.87 or 0.3 < dl(i , j ) < 0.1 , and only particles with 4 bonds are considered crystalline .
systems were considered to have crystallized spontaneously when more than 10% of the system was crystalline .
note that although the q6 based order parameter is sensitive to multiple crystal structures , visual inspection of the detected clusters consistently showed a bcc structure in all cases .

Answer:
one of the most controversial hypotheses for explaining the origin of the thermodynamic anomalies characterizing liquid water postulates the presence of a metastable second - order liquid - liquid critical point [ 1 ] located in the  no - man s land  [ 2 ] . in this scenario ,
 two liquids with distinct local structure emerge near the critical temperature . unfortunately , since spontaneous crystallization is rapid in this region , experimental support for this hypothesis relies on significant extrapolations , either from the metastable liquid or from amorphous solid water [ 3 , 4 ] .
 although the liquid - liquid transition is expected to feature in many tetrahedrally coordinated liquids , including silicon [ 5 ] , carbon [ 6 ] and silica , even numerical studies of atomic and molecular models have been unable to conclusively prove the existence of this transition .
 here we provide such evidence for a model in which it is possible to continuously tune the softness of the interparticle interaction and the flexibility of the bonds , the key ingredients controlling the existence of the critical point .
 we show that conditions exist where the full coexistence is thermodynamically stable with respect to crystallization .
 our work offers a basis for designing colloidal analogues of water exhibiting liquid - liquid transitions in equilibrium , opening the way for experimental confirmation of the original hypothesis .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
patients with conditions such as psoriasis , eczema , and skin cancer frequently face psychologic challenges which , in turn , impact their social functioning and the kind of life that they lead .
patients may experience fearful anticipation of interaction with others , even when symptoms are not present , and develop avoidance - coping mechanisms .
this may prevent them from partaking fully , or at all , in social and recreational activities or employment .
ultimately , visible symptoms may change how patients see themselves and how they perceive their future .
multiple studies reveal consistently poorer quality of life and psychosocial functioning scores among patients with visible dermatologic skin conditions compared with those who do not have such conditions [ 25 ] .
the incidence of psychosocial comorbidities among such patients is high , as evidenced by a study which found that the risks of depression , anxiety , and suicidality attributable to psoriasis were 11.8 , 8.1 , and 0.4 per 1000 person  years , respectively ( table  1 ) .table  1the attributable risk of psoriasis for diagnosis with depression , anxiety , and suicidality mild psoriasissevere psoriasisall psoriasisdepression  attributable risk per 1000 person - years11.525.511.8anxiety  attributable risk per 1000 person - years8.08.18.1suicidality  attributable risk per 1000 person - years0.40.40.4reproduced with permission from arch dermatol .
all rights reserved
 adjusted for age and sex
  the attributable risk of psoriasis for diagnosis with depression , anxiety , and suicidality   reproduced with permission from arch dermatol
all rights reserved
 adjusted for age and sex the dermatologist can play an important role in helping patients to overcome such substantial challenges and improve their overall quality of life .
we discuss several important considerations and propose strategies to assist dermatologists in addressing the important psychosocial side of treatment in patients with visible skin conditions .
studies have shown that successful treatment , which improves the patient s symptoms and changes their physical appearance , can lead to improvement in psychologic symptoms and a better quality of life [ 2 , 6 ] . however ,
it is important to note that , sometimes , greater life satisfaction is achieved by accepting that perhaps some symptoms will remain or recur , even if a patient generally responds well to treatment .
such acceptance involves acknowledging the existence of symptoms , but frees up the patient to pursue a meaningful life that is not overly limited by their condition .
it is also crucial that patients are provided with the tools to accept their remaining symptoms and to reduce the impact of these on everyday life .
as a clinician , one is familiar with the broad spectrum of available treatment options and the tools used to objectively measure outcomes in a clinical and/or academic setting .
treatment may be deemed successful if improvements in physical symptoms are in line with the results one would typically observe in other patients , or those that have been reported in clinical trials .
however , it is important to remember that other factors may influence the patient s own perception of treatment success .
patients have their own preferences and priorities regarding what treatment outcomes are more important to them .
for example , one patient may favor reduction or elimination of signs of disease that are visible to others when wearing typical clothes ( which may change with the season ) , whereas another patient may be more interested in reducing their level of physical discomfort .
patients satisfaction is strongly influenced by their initial expectations and the changes they were expecting to see , as well as those of their family and friends ; objective measures of symptom improvement may be less important to them . therefore , when evaluating treatment options , it is important to consider asking the patient what outcomes are most important to them and to discuss what it is reasonably possible to achieve .
as such , a broad outcome measure that includes psychosocial and overall quality of life measures , in addition to symptom remission , would be of particular value .
, clinicians may wish to discuss expected outcomes before treatment is initiated , including the degree of symptom improvement that can realistically be expected , the likelihood of success , and the timescales involved .
this would ideally be a two - way conversation , in which the clinician could ask the patient to explain their hopes and expectations as a result of their treatment .
there are several ways in which realistic expectations ( i.e. not too high and not too low ) will result in the best outcome for the patient .
if expectations are sufficiently high , a patient is more likely to be willing to initiate treatment and remain compliant , as they will be confident that they will eventually see an improvement in their symptoms .
similarly , if they have a tempered understanding of the expected degree of improvement , and when this may occur , they will be more likely to adhere to treatment without getting discouraged by seemingly poor results .
this is especially important in the case of complicated regimens , such as those associated with frequent or inconvenient drug administration , those that involve some degree of pain or discomfort , or those in which extensive treatment is required before symptoms begin to improve .
secondly , appropriate expectations can help a patient and their family to know when they need to return to the clinician and ask for a different treatment approach .
such a dynamic , interactive relationship between the clinician and the patient can ensure that the patient s needs are being met wherever possible , and may reduce unnecessary time and costs associated with treatment that is inappropriate or ineffective for that person . finally , focusing on the broad improvement of patient quality of life , and not just on the management of visible symptoms , may help to reduce the often excessive pressure placed on healthcare providers by patients with unrealistic expectations for improvement .
this can improve the clinician 's own sense of job satisfaction , as well as the overall relationship between the clinician and the patient .
impairment , however , is defined as the suffering that can be caused by symptoms , and may be physical , psychologic , and/or social .
the degree of impairment caused by a given symptom is often different in different people ; in fact , a patient can have a severe symptom but not be impaired by it at all .
conversely , a different patient may be greatly impaired by symptoms of relatively mild severity , with a tremendously negative impact on their life .
for example , an insecure teenager may feel extremely self - conscious about minor acne and avoid some social situations , whereas a confident young adult with much worse symptoms may hardly think about them .
when it comes to reducing the psychologic impact of a dermatologic condition and improving the patient s quality of life , it is crucial that we address impairment and not just symptoms .
it is possible for a patient to actively refuse to be unnecessarily limited by their symptoms , rather than be passively resigned to them .
however , support and encouragement are often needed in order for a patient to achieve this . as clinicians
, we have the opportunity to encourage patients to live  a big life , i.e. a life that is fulfilling , rewarding , meaningful , and interesting , and that has a positive impact on the world , in which the person accomplishes most of what they set out to do . in turn
, the patient may strive to be the person that they want to be , regardless of their health status .
other professionals , such as nurses , psychotherapists , or counsellors , who may be involved in the wider healthcare circle of a patient , can also assist in this regard . in some cases , an overly negative response to symptoms
can be indicative of low self - esteem , anxiety , or depression , which can warrant a referral to a mental health professional to help the patient cope , not only with their dermatologic condition , but also with other matters .
we can help patients to redefine themselves by asking the question ,  what would / could you do if you did not have these symptoms ?
it should be emphasized that , although symptoms may affect how a patient lives their life , symptoms do not necessarily need to rule a patient s life .
we can also help patients to understand that tolerating discomfort may allow them to pursue more interesting goals in life .
mental health professionals can help more limited patients to learn better coping methods to deal with sometimes debilitating discomfort .
patients should , of course , be encouraged to follow the treatment regimen , and active engagement with the clinician will enable the patient to feel that they are in control of their condition and their treatment program .
however , we can emphasize to patients that it is important not to wait for complete symptom remission before pursuing a fulfilled life .
some patients restrict their social engagement because they feel self - conscious about their visible symptoms and do not know how to respond to people s questions about them , such as why they look that way , or whether the condition is contagious .
helping patients find the right words to explain their visible symptoms to others can help them feel more comfortable going out into the world .
this is particularly true of situations in which the patient is likely to encounter people who are more likely to make inappropriate comments , ask personal questions , or make incorrect assumptions , such as that the condition is highly infectious .
it is easier for the patient to cope and feel confident in such situations if they have an appropriate and informed range of responses prepared in advance .
patients can choose to share personal information , but they also have the right not to do so .
visible medical conditions such as psoriasis , eczema , and skin cancer often have a substantial psychologic and social impact on patients .
however , through appropriate discussion and interaction with a patient , the dermatologist can play an important role in helping to reduce this impact , potentially improving the patient s overall quality of life .
it is important to discuss expected outcomes before treatment is initiated , in order to ensure that realistic expectations are in place . it may also be beneficial to discuss whether total symptom relief is a necessary component to living a better life . in addition ,
helping patients to find the right words to explain their visible symptoms to others can help them feel less self - conscious and more confident in a public setting . helping patients to come to terms with their condition , and helping them to build the skills required to reduce the psychosocial impact of their condition
, may mean that they are more equipped to go out into the world and pursue a more meaningful life .
this article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors .

Answer:
skin conditions such as psoriasis , eczema , and skin cancer often have a substantial psychologic and social impact on our patients .
 some of these patients limit their life because they feel self - conscious about their symptoms .
 sometimes , greater life satisfaction comes from accepting that perhaps some symptoms will remain or recur , even in an individual who responds well to treatment .
 this acceptance involves acknowledging the existence of symptoms , thereby allowing the patient to pursue a meaningful life that is not overly limited by their potential presence .
 this is not only liberating for the patient but also for the medical professional , who can sometimes feel pressured by patients unrealistic expectations to achieve symptom reductions that are not possible .
 we discuss how to talk with patients about their expectations regarding treatment and whether relief of symptoms is a necessary component to living a better life .
 helping patients to find the right words to explain their visible symptoms to others can sometimes help them feel less self - conscious in public settings and thereby more comfortable going out into the world to pursue a meaningful life .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
for the past 50 years disulfiram is the commonly prescribed drug for the treatment of alcohol dependence .
important side effects of disulfiram are hepatological , dermatological , neurological ( polyneuritis , encephalopathy)1,2 ) and psychiatric in nature .
psychiatric manifestations include confusion , loss of memory , psychosis,36 ) mania with psychotic symptoms.7,8 ) disulfiram s major metabolite diethyldithiocarbamate is an inhibitor of dopamine - betahydroxylase ( dbh ) , an enzyme that catalyzes the metabolism of dopamine ( da ) to norepinephrine ( ne).9 ) by inhibiting this metabolic pathway from da to ne in the central nervous system , disulfiram results in an increase of da concentrations in mesolimbic system resulting in psychosis .
alcoholics who developed psychotic symptoms during disulfiram treatment are found to have low levels of amine and monoamine oxidase , suggesting dbh blockage.10 ) we present a case of 32-year - old male who developed psychosis with the use of disulfiram .
a 32-year - old male without past of psychiatric and neurological illness reported to psychiatry outpatient department with complaint of daily alcohol intake of 250750 ml ( 40% alcohol by volume ) for the last 5 years . with the informed consent of the patient
, disulfiram was administered at the dosage of 250 mg twice daily for 1 month , while the patient abstained from alcohol .
then the patient presented complaint of fearfulness , suspiciousness , easy irritability , muttering to self , decreased sleep for last one month .
haematological and biochemical indices were within normal limits . on mental status examination delusion of persecution and auditory
his fearfulness , suspiciousness , irritability , muttering to self and impaired sleep gradually improved over a period of 10 days .
risk factors for development of disulfiram related psychotic symptoms include past history or family history of psychosis , overly rapid increase in dosage or greater than recommended total dosage , old age , impaired liver function and concurrent dopaminergic medications or psycho - stimulant abuse.5,11 ) our patient has family history of schizophrenia in his father .
his psychotic symptoms improved after stoppage of disulfiram and use of lorazepam tablet only without any additional requirement of anti - psychotic treatment .
these factors support the association between with disulfiram use and emergence of psychotic symptoms in our patient .
the usual recommended initial dosage is 500 mg per day for the first 1 or 2 weeks , followed by a maintenance dosage of 250 mg per day.12 ) disulfiram related psychosis usually involve either therapeutic or higher than recommended dosages.13 ) our patient has developed psychotic symptoms with 500 mg per day of disulfiram .
we recommend that disulfiram should be used at the lowest effective dose , possibly 250 mg daily .
our case highlights the relevance of a careful history of patient s symptoms and family history that should be performed before starting treatment with disulfiram and caution should be taken while prescribing disulfiram for patients with personal and familial antecedents of psychosis .
disulfiram - related psychiatric complications are reported to be more prevalent in eastern countries,3 ) which suggests that genetic factors may play a role in disulfiram induced psychosis .

Answer:
disulfiram is the commonly prescribed drug for the treatment of alcohol dependence .
 it s major metabolite ( diethyldithiocarbamate ) is an inhibitor of dopamine - betahydroxylase , an enzyme that catalyzes the metabolism of dopamine to norepinephrine resulting in psychosis .
 we recommend that disulfiram should be used at the lowest effective dose , possibly 250 mg daily and caution should be taken while prescribing disulfiram for patients with personal and familial antecedents of psychosis .