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2. Empagliflozin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
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Abani, O, Abbas, A, Abbas, F, Abbas, J, Abbas, K, Abbas, M, Abbasi, S, Abbass, H, Abbott, A, Abdallah, N, Abdelaziz, A, Abdelfattah, M, Abdelqader, B, Abdul, A, Abdul, B, Abdul, S, Abdul Rasheed, A, Abdulakeem, A, Abdul-Kadir, R, Abdullah, A, Abdulmumeen, A, Abdul-Raheem, R, Abdulshukkoor, N, Abdusamad, K, Abed El Khaleq, Y, Abedalla, M, Abeer Ul Amna, A, Abel, L, Abernethy, K, Abeywickrema, M, Abhinaya, C, Abidin, A, Aboaba, A, Aboagye-Odei, A, Aboah, C, Aboelela, H, Abo-Leyah, H, Abouelela, K, Abou-Haggar, A, Abouibrahim, M, Abousamra, A, Abouzaid, M, Abraham, M, Abraham, T, Abraheem, A, Abrams, J, Abrams, R, Abu, HJ, Abu-Arafeh, A, Abubacker, SM, Abung, A, Abusamra, Y, Aceampong, Y, Achara, A, Acharya, D, Acheampong, F, Acheampong, P, Acheampong, S, Acheson, J, Achieng, S, Acosta, A, Acquah, R, Acton, C, Adabie-Ankrah, J, Adair, P, Adam, AS, Adam, F, Adam, M, Adamali, H, Adamczyk, M, Adams, C, Adams, D, Adams, K, Adams, L, Adams, N, Adams, R, Adams, T, Adamu-Ikeme, L, Adatia, K, Adcock, K, Addai-Boampong, L, Addo, A, Adeagbo, O, Adebiyi, A, Adedeji, O, Adegeye, Y, Adegoke, K, Adell, V, Adenwalla, S, Adeoye, FW, Adesemoye, OA, Adewunmi, EO, Adeyanju, A, Adeyemi, J, Adeyemo, T, Adhikari, B, Adhikari, SA, Adhikary, R, Aditya, A, Adjepong, P, Adkins, G, Adnan, A, Adriaanse, M, Aeron-Thomas, J, Affleck, D, Afnan, C, Afridi, M, Afrim, P, Afriyie, FA, Aftab, ZA, Afum-Adjei Awuah, A, Agarwal, M, Agasiya, PN, Agbeko, R, Agbo, C, Aggarwal, S, Aghababaie, A, Aguilar Jimenez, L, Agyekum, JA, Agyen, K, Ahadome, EK, Ahamed Sadiq, S, Ahammed Nazeer, MH, Ahmad, M, Ahmad, S, Ahmed, A, Ahmed, BAR, Ahmed, B, Ahmed, F, Ahmed, H, Ahmed, I, Ahmed, K, Ahmed, L, Ahmed, M, Ahmed, MC, Ahmed, MS, Ahmed, N, Ahmed, O, Ahmed, RA, Ahmed, R, Ahmed, S, Ahmed, SG, Ahmed, SH, Ahmed Ali, R, Ahmed Mohamud, B, Ahmer, S, Ahonia, A, Aidoo, C, Aiken, C, Ail, D, Ainsworth, M, Aissa, M, Aitken, L, Ajay, B, Ajibode, A, Ajmi, A, Akhtar, N, Akili, S, Akinbiyi, B, Akindolie, O, Akinfenwa, Y, Akinkugbe, O, Akinpelu, I, Akram, M, Aktinade, O, Akudi, U, Al Aaraj, ASAR, Al Balushi, A, Al Dakhola, M, Al Swaifi, A, Al-Abadi, E, Alabi, A, Aladangady, N, Alafifi, M, Alam, A, Alam, S, Al-Asadi, A, Alatzoglou, K, Albert, P, Albertus, A, Albon, L, Alcala, A, Alcorn, G, Alcorn, S, Aldana, A, Alderdice, D, Aldesouki, A, Aldouri, R, Aldridge, J, Aldridge, N, Ale, RM, Alegria, A, Alexander, A, Alexander, C, Alexander, J, Alexander, PDG, Al-fori, J, Alghazawi, L, Alhabsha, O, Al-Hakim, B, Alhameed, R, Al-Hayali, M, Al-Hity, S, Ali, A, Ali, FR, Ali, J, Ali, M, Ali, MS, Ali, N, Ali, O, Ali, R, Ali, S, Aliberti, E, Alin, J, Alina, A, Alipustain, A, Alisjahbana, B, Aliyuda, F, Alizadeh, K, Al-Jibury, M, Al-Juboori, S, Al-Khalil, M, Alkhudhayri, A, Alkhusheh, M, Allan, F, Allan, N, Allanson, A, Allcock, R, Allen, E, Allen, J, Allen, K, Allen, L, Allen, P, Allen, R, Allen, S, Allen, T, Alli, A, Allison, K, Allman, B, Allsop, HK, Allsop, L, Allsup, D, Almahroos, AFT, Al-Moasseb, H, Al-Obaidi, M, Alomari, L, Al-Rabahi, A, Al-Ramadhani, B, Al-Saadi, Z, Al-Sammarraie, R, Alshaer, I, Al-Shahi Salman, R, Al-Shamkhani, W, Alsheikh, F, Al-Sheklly, B, Altaf, S, Alty, A, Alvarez, M, Alvarez Corral, M, Alveyn, E, Alzetani, M, Amamou, S, Amar, N, Ambalavanan, S, Ambrogetti, R, Ambrose, C, Ameen, A, Amelia Ganefianty, A, Ames, K, Amezaga, MR, Amin, A, Amin, K, Amin, S, Amin, T, Amit, B, Amjad, A, Amjad, N, Amoah-Dankwa, J, Amoako-Adusei, A, Amosun, V, Amsal, M, Amsha, K, Amuasi, J, Amutio Martin, N, Amy, P, Anada, A, Anand, A, Anandappa, S, Anantapatnaikuni, SD, Andari, NKN, Anderson, E, Anderson, J, Anderson, L, Anderson, M, Anderson, N, Anderson, R, Anderson, S, Anderson, W, Andreou, P, Andrews, A, Andrews, J, Aneke, K, Ang, A, Ang, WW, Angel, T, Angela, A, Angelini, P, Anguvaa, L, Anichtchik, O, Anim-Somuah, M, Aniruddhan, K, Annett, J, Anning, L, Ansah, M, Anstey, PJ, Anstey, R, Anthony, A, Anthony-Pillai, A, Antill, P, Antonina, Z, Anu, V, Anwar, M, Anwar, S, Apetri, E, Apostolopoulos, A, Appleby, S, Appleyard, D, Aquino, MF, Araba, B, Aransiola, S, Araujo, M, Archer, A, Archer, D, Archer, S, Arcoria, D, Ardley, C, Arhin-Sam, G, Arias, A-M, Aribike, O, Arimoto, R, Arisanti, NLPE, Arkley, C, Armah, C, Armata, I, Armistead, J, Armitage, A, Armstrong, C, Armstrong, M, Armstrong, S, Armstrong, W, Armtrong, P, Arndt, H, Arnison-Newgass, C, Arnold, D, Arnold, R, Arnott, A, Arora, D, Arora, K, Arora, P, Arora, R, Arter, A, Arthur, A, Artini, NM, Arumaithurai, A, Arya, A, Arya, R, Aryal, D, Asandei, D, Asare, GA, Asghar, A, Asghar, M, Ashab, A, Ashbrook-Raby, C, Ashby, H, Ashcroft, J, Ashcroft, S, Asher, G, Ashfak, Z, Ashfaq, A, Asiamah, HA, Ashish, A, Ashley, D, Ashman-Flavell, S, Ashok, S, Ashour, A-E-A, Ashraf, MZ, Ashraf, S, Ashraq, MB, Ashton, D, Ashton, S, Ashworth, A, Ashworth, FJ, Ashworth, R, Aslam, A, Aslam, I, Aslam, S, Aslett, L, Asogan, H, Asrar, A, Assaf, O, Astin-Chamberlain, R, Atabudzi, YE, Athavale, P, Athorne, D, Atkins, B, Atkins, C, Atkins, S, Atkinson, J, Atkinson, V, Atomode, A, Atraskiewicz, B, Attia, AA, Attubato, E, Attwood, M, Aubrey, P, Auer, Z, Aujayeb, A, Aung, AT, Aung, H, Aung, HWW, Aung, KK, Aung, KT, Aung, N, Aung, Y, Aung, ZM, Austin, E, Austin, K, Auwal, A, Avari, M, Avery, M, Aveyard, N, Avis, J, Aviss, G, Avram, C, Avram, P, Awadelkareem, A, Awadzi, G, Awaly, M, Awan, A, Awisi, S, Aya, A, Ayaz, E, Ayerh, JM, Ayers, A, Azam, J, Azeem, A, Azharuddin, M, Aziz, A, Aziz, G, Aziz, I, Aziz, N, Azkoul, A, Azman Shah, A, Azzopardi, G, Azzoug, H, Babatunde, F, Babi, M, Babiker, B, Babington, G, Babirecki, M, Babores, M, Babs-Osibodu, AO, Bac, T, Bacciarelli, S, Bachar, R, Bachour, M-E, Bachti, A, Bacon, G, Bacon, J, Badal, B, Badat, A, Bader, M, Badhan, GR, Badhrinarayanan, S, Bae, JP, Baggaley, A, Baggott, A, Bagley, G, Bagmane, D, Bagshaw, L, Bahadori, K, Bahurupi, Y, Bailey, A, Bailey, J, Bailey, K, Bailey, L, Bailey, MA, Bailey, M, Bailey, P, Bailey, S, Baillie, H, Baillie, JK, Bain, J, Bains, V, Baird, D, Baird, E, Baird, K, Baird, S, Baird, T, Baird, Y, Bajandouh, A, Baker, DC, Baker, E, Baker, J, Baker, K, Baker, M, Baker, R, Baker, T-A, Baker, V, Bakere, H, Bakerly, N, Baker-Moffatt, M, Bakhai, A, Bakhtiar, N, Bakoulas, P, Bakthavatsalam, D, Balachandran, N, Balan, A, Balasingam, P, Balaskas, T, Balasubramaniam, M, Balatoni, N, Balcombe, A, Baldwin, A, Baldwin, C, Baldwin, D, Baldwin, F, Baldwin-Jones, R, Bale, N, Balfour, J, Ball, M, Ball, Ro, Ballard, K, Balluz, I, Balmforth, C, Balogh, E, Baltmr, A, Baluwala, A, Bambridge, G, Bamford, A, Bamford, P, Bamgboye, A, Bancroft, E, Bancroft, H, Banda, J, Bandaru, K, Bandi, S, Bandla, N, Bandyopadhyam, S, Banerjee, A, Banerjee, R, Bang, P, Baniya, S, Bani-Saad, O, Banks, H, Banks, L, Banks, P, Bann, C, Bannister, H, Bannister, O, Banton, L, Bao, T, Baptist, M, Baqai, T, Baral, AM, Baral, SC, Baramova, D, Barber, R, Barbon, E, Barbosa, M, Barbour, J, Barclay, A, Barclay, C, Bardsley, G, Bareford, S, Bari, S, Barimbing, M, Barker, A, Barker, D, Barker, E, Barker, H, Barker, J, Barker, L, Barker, O, Barker-Williams, K, Barkha, S, Barla, J, Barlow, G, Barlow, R, Barlow, V, Barnacle, J, Barnard, A, Barnes, D, Barnes, N, Barnes, R, Barnes, T, Barnetson, C, Barnett, A, Barnett-Vanes, A, Barning, PG, Barnsley, W, Barr, A, Barr, D, Barr, J, Barr, C, Barratt, N, Barratt, S, Barrera, M, Barrett, A, Barrett, Fi, Barrett, J, Barrett, S, Barrow, E, Bartholomew, J, Barthwal, MS, Bartlett, C, Bartlett, G, Bartlett, J, Bartlett, L, Bartley, S, Bartolmeu-Pires, S, Barton, A, Barton, G, Barton, J, Barton, L, Barton, R, Baruah, R, Baryschpolec, S, Bashir, H, Bashyal, A, Basker, B, Basnet, S, Basnyat, B, Basoglu, A, Basran, A, Bassett, J, Bassett, G, Bassford, C, Bassoy, B, Bastion, V, Bastola, A, Basumatary, A, Basvi, P, Batac, JA, Bataduwaarachchi, VR, Bate, T, Bateman, HJ, Bateman, K, Bateman, V, Bates, E, Bates, H, Bates, M, Bates, S, Batham, S, Batista, A, Batla, A, Batra, D, Batty, H, Batty, T, Batty, A, Baum, M, Baumber, R, Bautista, C, Bawa, F, Bawa, T, Bawani, FS, Bax, S, Baxter, M, Baxter, N, Baxter, Z, Bayes, H, Bayo, L-A, Bazari, F, Bazaz, R, Bazli, A, Beacham, L, Beadles, W, Beadon, K, Beak, P, Beale, A, Beard, K, Bearpark, J, Beasley, A, Beattie, S, Beaumont, K, Beaumont-Jewell, D, Beaver, T, Beavis, S, Beazley, C, Beck, S, Beckett, V, Beckitt, R, Beckley, S, Beddall, H, Beddows, S, Beeby, D, Beeby, S, Beech, G, Beecroft, M, Beer, N, Beer, Sa, Beety, J, Bega, G, Begg, A, Begg, S, Beghini, S, Begum, A, Begum, S, Behan, T, Behrouzi, R, Beishon, J, Beith, C, Belcher, J, Belfield, H, Belfield, K, Belgaumkar, A, Bell, D, Bell, G, Bell, J, Bell, L, Bell, N, Bell, P, Bell, S, Bellamu, J, Bellamy, M, Bellamy, T, Bellini, A, Bellis, A, Bellis, F, Bendall, L, Benesh, N, Benetti, N, Bengu, SA, Benham, L, Benison-Horner, G, Benkenstein, S, Benn, T, Bennett, A, Bennett, C, Bennett, D, Bennett, G, Bennett, K, Bennett, L, Bennett, MR, Bennett, S, Bennion, K, Benoy, G, Benson, V, Bentley, A, Bentley, J, Benton, I, Beranova, E, Beresford, M, Bergin, C, Bergstrom, M, Bernatoniene, J, Berriman, T, Berry, Z, Best, F, Best, K, Bester, A-M, Beuvink, Y, Bevan, E, Bevins, S, Bewick, T, Bexley, A, Beyatli, S, Beynon, F, Bhadi, A, Bhagani, S, Bhakta, S, Bhalla, R, Bhandal, K, Bhandari, A, Bhandari, LN, Bhandari, S, Bhanich Supapol, J, Bhanot, A, Bhanot, R, Bhasin, S, Bhat, A, Bhat, P, Bhatnagar, R, Bhatt, K, Bhayani, J, Bhojwani, D, Bhuie, P, Bhuiyan, MS, Bhuiyan, S, Bibby, A, Bibi, F, Bibi, N, Bibi, S, Bicanic, T, Bidgood, S, Bigg, J, Biggs, S, Biju, A, Bikov, A, Billingham, S, Billings, J, Binh, P, Binns, A, BinRofaie, M, Bintcliffe, O, Birch, C, Birch, J, Birchall, K, Bird, S, Birt, M, Bishop, C, Bishop, K, Bishop, L, Bisnauthsing, K, Biswas, N, Bittaye, M, Biuk, S, Blachford, K, Black, E, Black, H, Black, K, Black, M, Black, P, Black, V, Blackgrove, H, Blackledge, B, Blackler, J, Blackley, S, Blackman, H, Blackstock, C, Blair, C, Blakemore, F, Blamey, H, Bland, A, Blane, S, Blankley, S, Blaxill, P, Blaylock, K, Blazeby, J, Blencowe, N, Bloom, B, Bloomfield, J, Bloss, A, Blowers, A, Blows, S, Bloxham, H, Blrd, S, Blundell, L, Blunsum, A, Blunt, M, Blunt, T, Blyth, I, Blyth, K, Blythe, A, Blythe, K, Boahen, KA, Boampoaa, M, Board, S, Boatemah, E, Bobie, B, Bobruk, K, Bodalia, PN, Bodasing, N, Boden, M, Bodenham, T, Boehmer, G, Boffito, M, Bohanan, K, Bohmova, K, Bohnacker, N, Bokhandi, S, Bokhar, M, Bokhari, S, Bokhari, SO, Bokobza, I, Boles, A, Bolger, C, Bonaconsa, C, Bond, C, Bond, H, Bond, S, Bond, T, Bone, A, Boniface, G, Bonney, J, Bonney, L, Booker, L, Boot, S, Boothroyd, M, Borbone, J, Borman, N, Bosence, S, Bostock, K, Botting, N, Bottrill, F, Bouattia, H, Bough, L, Boughton, H, Boult, Z, Boumrah, T, Bourke, M, Bourke, S, Bourne, M, Bousfield, R, Boustred, L, Bowes, A, Bowker, P, Bowker, T, Bowler, H, Bowman, L, Bowman, S, Bowmer, R, Bowring, A, Bowyer, H, Boyd, A, Boyd, J, Boyd, L, Boyer, N, Boyle, N, Boyle, P, Boyle, R, Boyles, L, Brace, L, Bracken, A, Bradder, J, Bradley, CJ, Bradley, P, Bradley-Potts, J, Bradshaw, L, Bradshaw, Z, Brady, C, Brady, R, Brady, S, Braga Sardo, P, Braganza, D, Braithwaite, M, Brammer, S, Branch, M, Brankin-Frisby, T, Brannigan, J, Brattan, S, Bray, F, Bray, N, Brazil, M, Brear, L, Brear, Tr, Brearey, S, Bremner, L, Brend, M, Bresges, C, Bressington, C, Bretland, G, Brewer, C, Bridgett, M, Bridgwood, G, Brigham, S, Bright, J, Brightling, C, Brigstock, T, Brimfield, L, Brinksman, P, Brinkworth, E, Brittain-Long, R, Britten, V, Britton, H, Broad, L, Broadhead, S, Broadhurst, R, Broadley, A, Broadway, M, Brockelsby, C, Brocken, M, Brockley, T, Brodsky, M, Brogan, F, Brohan, L, Brokke, F, Brolly, J, Bromley, D, Brooke-Ball, H, Brooker, V, Brookes, M, Brooking, D, Brooks, A, Brooks, D, Brooks, J, Brooks, K, Brooks, N, Brooks, P, Brooks, R, Brooks, S, Broom, M, Broomhead, N, Broughton, C, Broughton, N, Brouns, M, Brown, A, Brown, C, Brown, E, Brown, H, Brown, J, Brown, L, Brown, N, Brown, P, Brown, R, Brown, S, Brown, T, Browne, B, Browne, C, Browne, D, Browne, M, Brownlee, S, Brraka, A, Bruce, J, Bruce, M, Brudlo, W, Brunchi, A, Brunskill, N, Brunton, A, Brunton, M, Bryant, M, Bryden, E, Brzezicki, H, Buazon, A, Buch, MH, Buchan, R, Buchanan, R, Buche, D, Buck, A, Buck, L, Buckland, M, Buckley, C, Buckley, L, Buckley, P, Buckley, S, Buckman, C, Budds, A, Bugg, G, Bujazia, R, Bukhari, M, Bukhari, S, Bulbulia, R, Bull, A, Bull, D, Bull, K, Bull, R, Bull, Th, Bullock, E, Bullock, S, Bulteel, N, Bumunarachchi, K, Bungue-Tuble, R, Burbidge, O, Burchett, C, Burda, D, Burden, C, Burden, TG, Burgess, Mi, Burgess, R, Burgess, S, Burhan, E, Burhan, H, Burke, H, Burke, K, Burman, A, Burnard, S, Burnett, C, Burnett, S, Burns, A, Burns, C, Burns, J, Burns, K, Burrage, D, Burrows, K, Burston, C, Burton, A, Burton, B, Burton, F, Burton, H, Burton, M, Butar butar, M, Butcher, D, Butler, A, Butler, E, Butler, J, Butler, P, Butler, S, Butt, A-T, Butt, M, Butt, MM, Butterworth, C, Butterworth-Cowin, N, Buttery, R, Buttle, T, Button, H, Buttress, D, Bye, H, Byrne, J, Byrne, W, Byrne-Watts, V, Cabandugama, A, Cabrero, L, Caddy, S, Cade, R, Cadwgan, A, Cahilog, Z, Cahyareny, A, Cairney, D, Calderwood, J, Caldow, D, Cale, E, Calisti, G, Callaghan, D, Callaghan, J, Callens, C, Callum, D, Calver, C, Cambell-Kelly, M, Camburn, T, Cameron, DR, Cameron, E, Cameron, F, Cameron, S, Camm, C, Cammack, FD, Campbell, A, Campbell, B, Campbell, D, Campbell, H, Campbell, J, Campbell, K, Campbell, M, Campbell, R, Campbell, W, Campbell Hewson, Q, Camsooksai, J, Canclini, L, Candido, SM, Candlish, J, Caneja, C, Cann, A, Cann, J, Cannan, R, Cannon, A, Cannon, E, Cannon, M, Cannon, P, Cannons, V, Canonizado, E, Cantliff, J, Cap, N, Caplin, B, Capocci, S, Caponi, N, Capp, A, Capstick, R, Capstick, T, Caraenache, C, Card, A, Cardwell, M, Carey, C, Carey, R, Carley, S, Carlin, F, Carlin, T, Carmichael, S, Carmody, M, Carnahan, M, Caroline, C, Carpenter, J, Carr, S, Carrasco, A, Carrington, Z, Carroll, A, Carroll, P, Carson, R, Cart, C, Carter, E, Carter, J, Carter, M, Carter, N, Carter, P, Cartwright, D, Cartwright, J-A, Carty, C, Carty, L, Carungcong, J, Carver, C, Carver, E, Carver, R, Casey, S, Cassells, A, Castiello, T, Castle, G, Castles, B, Caswell, M, Catana, AM, Cate, H, Catelan Zborowski, A, Cathcart, S, Cathie, K, Catibog, D, Catley, C, Catlow, L, Caudwell, M, Cavazza, A, Cave, A, Cave, L, Cavinato, S, Cawa, F, Cawley, K, Caws, C, Cawthorne, K, Cendl, H, Century, H, Cernova, J, Cesay, M, Cetti, E, Chabane, S, Chablani, M, Chabo, C, Chacko, J, Chadwick, D, Chadwick, J, Chadwick, R, Chakkarapani, E, Chakraborty, A, Chakraborty, M, Chakravorty, M, Chalakova, P, Chalise, BS, Chalmers, J, Chalmers, R, Chamberlain, G, Chamberlain, S, Chambers, E, Chambers, J, Chambers, L, Chambers, N, Chan, A, Chan, C, Chan, E, Chan, M, Chan, K, Chan, P, Chan, R (P-C), Chan, XHS, Chandler, C, Chandler, H, Chandler, KJ, Chandler, S, Chandler, Z, Chandra, S, Chandran, N, Chandrasekaran, B, Chang, Y, Chanh, HQ, Chaplin, G, Chaplin, J, Chapman, G, Chapman, J, Chapman, K, Chapman, L, Chapman, M, Chapman, P, Chapman, T, Chappell, L, Charalambou, A, Charles, B, Charlton, D, Charlton, S, Chatar, K, Chatha, C, Chatterton, D, Chau, N, Chaube, R, Chaudhary, MYN, Chaudhary, B, Chaudhry, I, Chaudhry, Z, Chaudhuri, K, Chaudhuri, N, Chaudhury, M, Chauhan, A, Chauhan, RS, Chavasse, A, Chavasse, N, Chawla, V, Cheater, L, Cheaveau, J, Cheeld, C, Cheeseman, M, Chen, F, Chen, HM, Chen, T, Cheng, F, Cheng, LY, Cheng, Z, Chenoweth, H, Cheong, CH, Cherian, JJ, Cherian, S, Cherrie, M, Cheshire, H, Cheung, CK, Cheung, E, Cheung, K, Cheung, M, Cheyne, C, Chhabra, S, Chia, WL, Chiang, E, Chiapparino, A, Chicano, R, Chikara, G, Chikungwa, M, Chikwanha, ZA, Chilcott, G, Chilcott, S, Chilvers, A, Chimbo, P, Chin, KW, Chin, WJ, Chineka, R, Chingale, A, Chinonso, E, Chin-Saad, C, Chirgwin, M, Chisem, H, Chisenga, C, Chisholm, C, Chisnall, B, Chiswick, C, Chita, S, Chitalia, N, Chiu, M, Chiverton, L, Chivima, B, Chmiel, C, Choi, S, 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M, Thien, D, Thiri Phoo, N, Thirlwall, Y, Thirumaran, M, Thomas, A, Thomas, C, Thomas, E, Thomas, H, Thomas, J, Thomas, JL, Thomas, K, Thomas, L, Thomas, R, Thomas, S, Thomas, T, Thomas, V, Thomasson, K, Thomas-Turner, R, Thompson, C, Thompson, E, Thompson, F, Thompson, H, Thompson, J, Thompson, K, Thompson, L, Thompson, M, Thompson, O, Thompson, R, Thompson, Y, Thomson, BG, Thomson, N, Thorburn, P, Thorn, N, Thorne, C, Thorne, N, Thornton, A, Thornton, D, Thornton, J, Thornton, R, Thornton, S, Thornton, T, Thorpe, C, Thorpe, N, Thorpe, S, Thozthumparambil, P, Thrasyvoulou, L, Thraves, H, Thu, N, Thueux, G, Thuong, NTH, Thu-Ta, P, Thuy, D, Thwaiotes, V, Thwaites, CL, Thwaites, G, Tiberi, S, Tieger, S, Tierney, C, Tighe, M, Tilbey, S, Till, C, Tiller, A, Tiller, H, Timerick, J, Timlick, E, Timmins, A, Timmis, A, Timms, H, Timoroksa, A-M, Tinashe, S, Tingley, S, Tinker, N, Tinkler, H, Tinkler, M, Tipper, J, Tirumalai Adisesh, A, Tivenan, H, Tluchowska, K, T-Michael, H, Todd, A, Todd, J, Todd, S, Toffoletti, O, Tohfa, M, Tohill, S, Tolson, M, Tomas, A, Tomasova, N, Tomlin, S, Tomlins, S, Tomlinson, J, Tomlinson, K, Tonkin, J, Tonna, I, Toohey, C, Topham, K, Topping, M, Torokwa, A, Torrance, C, Touma, O, Tous Sampol, L, Tousis, R, Tout, M, Tovey, P, Towersey, G, Townley, J, Tozer, R, Tran, DK, Tran, H, Tran, HB, Tran, M, Tran, NB, Tran, VG, Tran, VK, Tranter, H, Travers, J, Travill, C, Traynor, S, Trethowan, L, Treus Gude, E, Trevelyan, M, Trewick, NA, Tridente, A, Trieu, H, Triggs, S, Trim, F, Trimmings, A, Trinick, T, Tripathy, S, Trivedi, K, Troedson, S, Tropman, E, Trotter, A, Trous, S, Trower, H, Trowsdale Stannard, M, Trudgill, N, Truell, R, Truman, N, Truslove, M, Trussell, S, Trussell, T, Tsakiridou, K, Tsang, C, Tsang, P, Tsawayo, T, Tsilimpari, KK, Tsinaslanidis, G, Tsitsi, M, Tso, S, Tucker, N, Tucker, S, Tudor, DE, Tufail, A, Tuff, J, Tuffney, J, Tully, R, Tulus Satriasih, T, Tunesi, G, Tung, D, Turbitt, K, Turel, R, Turgut, T, Turley, C, Turnbull, A, Turner, A, Turner, C, Turner, G, Turner, K, Turner, L, Turner, LC, Turner, M, Turner, P, Turner, S, Turner, V, Turner-bone, I, Turney, S, Turvey, J, Tweed, C, Tweed, D, Twemlow, R, Twohey, E, Tyagi, B, Tyagi, V, Tyer, A, Tyler, A, Tyler, J, Tyzack, A, Tzavaras, P, Tzinieris, I, Uddin, AW, Uddin, MS, Uddin, R, Ugoji, J, Ukaegbu, E, Ul Haq, M, Ul Hassan, W, Ul-Haq, Z, Ullah, S, Um, J, Umaipalan, A, Umate, A, Umeadi, J, Umeh, A, Umeojiako, W, Ummat, B, Underhill, E, Underwood, C, Underwood, J, Unsworth, A, Uppal, V, Uppal, VS, Upson, G, Ur Rasool, M, Uriel, A, Urruela, S, Uru, H, Usher, J, Usher, M, Usher, R, Usher-Rea, A, Ustianowski, A, Usuf, E, Utomo, FN, Uzu, H, Vaccari, LC, Vaghela, U, Vaidya, A, Vail, D, Valecka, B, Valentine, J, Valeria, B, Vallabhaneni, P, Valleri, T, Vallotton, N, Vamplew, L, Vamvakiti, E, Vamvakopoulos, J, Van Blydenstein, S, van Bruggen, L, van de Venne, M, van der Meer, A, van der Stelt, N, Van Doorn, R, van Koutrik, L, Van Loggerenberg, A, Vance-Daniel, J, Vancheeswaran, R, Vandeyoon, SI, Vankayalapati, P, Vanmali, P, Vansomeren, C, Van't Hoff, W, Vanya, KN, Vara, S, Vardy, SJ, Varghese, A, Varghese, M, Varney, W, Varnier, G, Varouxaki, A-N, Varquez, R, Vasadi, V, Vass, O, Vassell, K, Vasu, V, Vasudevan, V, Vatish, M, Vaughan, S, Vayalaman, H, Vayapooree, D, Vaz, C, Veale, N, Veerasamy, S, Velankar, S, Velauthar, L, Veli, N, Vella, N, Velugupati, A, Velusamy, A, Venables, I, Venditti, M, Venkataramakrishnan, R, Venn, R, Venter, M, Ventilacion, L, Vere, J, Veres, M, Vergnano, S, Verling, W, Verma, A, Vernall, R, Vernon, B, Vertue, M, Verueco, L, Verula, J, Veterini, A, Vethanayagam, N, Vettikumaran, S, Veys, L, Vickers, C, Victor, S, Victoria, S, Vidaillac, CP, Vidler, J, Vijayakumar, B, Vijayaraghavan Nalini, VW, Vilcinskaite, B, Vileito, A, Vilimiene, N, Vinall, L, Vinay, S, Vinayakarao, L, Vincent, O, Vincent, R, Virdee, P, Virgilio, E, Virk, AM, Visentin, E, Vitaglione, M, Vithian, K, Vittoria, S, Vivekananthan, S, Vlad, E, Vlies, B, von Oven, L, Vooght, C, Vu Thai, KT, Vutipongsatorn, K, Vuylsteke, A, Vyras, E, Wach, R, Wadams, B, Wadd, S, Waddington, N, Wade, P, Wadsley, J, Wadsworth, K, Wafa, SEI, Wagstaff, D, Wagstaff, L, Wahab, D, Wahbi, Z, Waheed Adigun, A, Waidyanatha, S, Waite, A, Wake, R, Wakefield, A, Wakeford, W, Wakinshaw, F, Waldeck, E, Walden, A, Walding, L, Waldron, A, Waldron, J, Wales, E, Wali, B, Walker, D, Walker, G, Walker, H, Walker, I, Walker, K, Walker, L, Walker, O, Walker, R, Walker, S, Wallace, G, Wallbutton, R, Wallen, J, Wallendszus, K, Waller, A, Waller, R, Wallis, G, Wallis, L, Wallis, M, Walmsley, E, Walsh, D, Walsh, E, Walsh, L, Walstow, D, Walter, D, Walters, A, Walters, H, Walters, J, Walton, E, Walton, L, Walton, M, Walton, O, Walton, S, Wan, M, Wanda, J, Wands, M, Wane, R, Wang, F, Wang, N, Wang, R, Wang, S, Warbrick, D, Warburton, S, Ward, C, Ward, D, Ward, E, Ward, H, Ward, J, Ward, L, Ward, N, Ward, R, Ward, T, Warden, SA, Wardere, G, Wardle, S, Wardy, H, Waring, G, Waring, S, Warmington, J, Warner, B, Warner, C, Warnock, L, Warran, S, Warren, J, Warren, L, Warren, R, Warren, Y, Warrender, D, Warren-Miell, H, Warris, A, Warwick, G, Wassall, H, Wasserman, S, Wasson, E, Watchorn, HJ, Waterfall, H, Waters, A, Waters, D, Waterstone, M, Watkin, A, Watkins, C, Watkins, E, Watkins, K, Watkins, L, Watson, A, Watson, AJR, Watson, E, Watson, F, Watson, JGR, Watson, L, Watson, P, Watson, R, Watson, K, Watters, M, Watterson, D, Wattimena, K, Watts, D, Watts, J, Watts, M, Waugh, V, Wayman, E, Wayman, M, Wazir, A, Weatherhead, M, Weatherly, N, Webb, C, Webb, H, Webb, K, Webb, S, Websdale, C, Webster, D, Webster, I, Webster, J, Webster, T, Wedlin, J, Wee, L, Weerakoon, R, Weerasinghe, T, Weeratunga, J, Weetman, M, Wei, S, Weichert, I, Welch, E, Welch, H, Welch, J, Welch, L, Welch, S, Welham, B, Weller, S, Wellings, L, Wells, B, Wellstead, S, Welsh, B, Welsh, R, Welters, I, Welton, R, Wenn, V, Wentworth, L, Wesonga, J, Wesseldine, K, West, J, West, M, West, R, West, S, Western, L, Westhead, R, Weston, H, Westwood, A, Westwood, K, Westwood, S, Wetherill, B, Wheaver, S, Wheeler, H, Whelan, B, Whelband, M, Whileman, A, Whitcher, A, White, A, White, B, White, C, White, D, White, J, White, K, White, M, White, N, White, S, White, T, Whitehead, C, Whitehorn, K, Whitehouse, A, Whitehouse, C, Whitehouse, T, Whiteley, J, Whiteley, L, Whiteley, S, Whitham, R, Whitlingum, G, Whitmore, D, Whittaker, E, Whittam, L, Whittington, A, Whittle, H, Whittle, R, Wiafe, E, Wiblin, L, Wickens, O, Widdrington, J, Wieboldt, J, Wieringa, H, Wiesender, C, Wiffen, L, Wight, A, Wignall, A, Wignall, C, Wilce, A, Wilcock, D, Wilcock, E, Wilcox, L, Wild, B, Wild, L, Wild, S, Wilde, M, Wilding, L, Wilding, P, Wildsmith, T, Wileman, J, Wiles, J, Wiles, K, Wilhelmsen, E, Wiliams, T, Wilkie, J, Wilkin, D, Wilkins, H, Wilkins, J, Wilkins, S, Wilkinson, I, Wilkinson, L, Wilkinson, N, Wilkinson, S, Wilkinson, T, Willetts, S, Williams, A, Williams, C, Williams, CV, Williams, D, Williams, E, Williams, G, Williams, H, Williams, J, Williams, K, Williams, M, Williams, P, Williams, R, Williams, S, Williams, T, Williamson, A, Williamson, C, Williamson, D, Williamson, J, Williamson, JD, Williamson, R, Williamson, H, Willis, E, Willis, H, Willis, J, Wills, L, Willsher, L, Willshire, C, Willson, F, Willson, J, Wilson, A, Wilson, B, Wilson, D, Wilson, I, Wilson, J, Wilson, K, Wilson, K-A, Wilson, L, Wilson, M, Wilson, S, Wilson, T, Win, KLY, Win, M, Win, T, Win, TT, Win, WYW, Winckworth, L, Winder, L, Winder, P, Winearl, S, Winmill, H, Winn, S, Winpenny, C, Winslow, H, Winter, H, Winter, J, Winter-Goodwin, B, Winterton, J, Winwood, H, Wischhusen, J, Wisdom, S, Wise, M, Wiselka, M, Wiseman, R, Wiseman, S, Wishart, S, WIshlade, T, Witele, E, Withers, N, Wittes, J, Wixted, D, Wodehouse, T, Wolf, W, Wolff, N, Wolffsohn, K, Wolf-Roberts, R, Wolodimeroff, E, Wolstencroft, A, Wong, A, Wong, C, Wong, C-H, Wong, C-M, Wong, E, Wong, JSY, Wong, KY, Wong, MY, Wong, N, Wong, S, Wong, T, Wongkyezeng, AA, Wood, A, Wood, C, Wood, D, Wood, F, Wood, G, Wood, H, Wood, J, Wood, L, Wood, M, Wood, S, Wood, T, Woodall, K, Woodfield, R, Woodford, C, Woodford, E, Woodford, J, Woodhead, L, Woodhead, T, Woodland, P, Woodman, M, Woodmansey, S, Woods, C, Woods, J, Woods, K, Woods, S, Woodward, Z, Woolcock, M, Wooldridge, G, Woolf, R, Woollard, C, Woollen, L, Woolley, E, Woolley, J, Woosey, D, Wootton, D, Wootton, J, Worley, D, Worton, S, Wraight, J, Wray, M, Wren, K, Wren, L, Wrey Brown, C, Wright, C, Wright, D, Wright, F, Wright, H, Wright, I, Wright, L, Wright, R, Wright, S, Wright, T, Wroe, C, Wroe, H, Wu, H, Wu, P, Wubetu, J, Wulandari, F, Wulandari, R, Wurie, S, Wyatt, C, Wyn-Griffiths, F, Wynter, I, Xavier, B, Xhikola, A, Xia, BE, Xia, Z, Yacoba, E, Yadav, S, Yakubi, M, Yan, M, Yanagisawa, Y, Yang, F, Yang, Y, Yanney, M, Yap, WL, Yaqoob, N, Yasmin, S, Yates, B, Yates, D, Yates, E, Yates, H, Yates, T, Yates, M, Ye, J, Yearwood Martin, C, Yein, K, Yelnoorkar, F, Yen, LM, Yeoh, A, Yeung, CY, Yew, P, Yewatkar, D, Ylquimiche Melly, L, Ynter, I, Yong, H, Yorke, J, Youens, J, Younes Ibrahim, A, Young, E, Young, G, Young, L, Yousafzar, A, Youssouf, S, Yousuf, A, Yovita, H, Yu, C, Yuan, JSJ, Yufaniaputri, N, Yung, B, Yusef, D, Yusef, S, Yusuf, I, Zafar, A-S, Zagalo, S, Zaher, S, Zahoor, A, Zainab, M, Zak, T, Zaki, K, Zakir, N, Zalewska, K, Zamalloa, A, Zaman, M, Zaman, S, Zamikula, J, Zammit, L, Zammit-Mangion, M, Zawadzka, M, Zayed, M, Zebracki, E, Zehnder, D, Zeidan, L, Zeinali, D, Zhang, J, Zhao, X, Zheng, D, Zhu, D, Zia, M, Zibdeh, O, Zill-E-Huma, R, Zin, ET, Zincone, E, Zindoga, G, Zinkin, E, Zinyemba, V, Zipitis, C, Zitter, L, Zmierczak, A, Zubikarai, G, Zubir, A, Zuhra, N, Zulaikha, R, Zulfikar, S, Zullo, C, and Zuriaga-Alvaro, A
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- 2023
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3. Diversity, equity and inclusion policy texts in Canadian agriculture
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Cameron, Dr. Bobby Thomas, primary, Ghaith, Dr. Ziad, additional, and Chilton, Dr. Lisa, additional
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- 2022
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4. The influence of model frameworks in spatial planning of regional climate-adaptive connectivity for conservation planning
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Choe, H, Choe, H, Keeley, ATH, Cameron, DR, Gogol-Prokurat, M, Hannah, L, Roehrdanz, PR, Schloss, CA, Thorne, JH, Choe, H, Choe, H, Keeley, ATH, Cameron, DR, Gogol-Prokurat, M, Hannah, L, Roehrdanz, PR, Schloss, CA, and Thorne, JH
- Abstract
Landscape connectivity improves species’ capacity to adapt to climate change. These models are increasingly needed and available for climate-change conservation planning. However, their relative strengths and weaknesses are unclear. We asked how well do the spatial outputs from four connectivity models intended to support climate change conservation agree? To understand the implications of selecting one or several approaches, we compared various combinations of four connectivity models for ecoregions in California, U.S.A. Two models are based on landscape structure, Land Facet Corridors and Omniscape, while two other models, Meta-Corridor Approach and Network Flow Analysis (NFA), use focal species’ range dynamics to determine connectivity. We also describe how each approach integrates climate-adaptive connectivity concepts. Variation in modeling methods, objectives, inputs, and landscape representations strongly affects the modeled connectivity patterns. For the region where all four models were run, almost three quarters of the landscape was selected by one or more models, but three or more agree for only 9.5% of the area, all of which is riparian. This emphasizes the importance of riparian areas for climate adaptation. We found NFA prioritized connections close to protected areas, while Meta-Corridor avoided higher cost agricultural and developed areas. The structural models agreed in areas with low human impact but Omniscape avoided areas of low topographic diversity and Land Facet Corridors avoided connections in areas with no protected areas. Connectivity models should be selected based on the conservation objectives, such as spatial scale to be implemented, and a combination of models may be best.
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- 2021
5. Hyperosmotic Infusion and Oxidized Surfaces Are Essential for Biofilm Formation of Staphylococcus capitis From the Neonatal Intensive Care Unit
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Qu, Y, Li, Y, Cameron, DR, Easton, CD, Zhu, X, Zhu, M, Salwiczek, M, Muir, BW, Thissen, H, Daley, A, Forsythe, JS, Peleg, AY, Lithgow, T, Qu, Y, Li, Y, Cameron, DR, Easton, CD, Zhu, X, Zhu, M, Salwiczek, M, Muir, BW, Thissen, H, Daley, A, Forsythe, JS, Peleg, AY, and Lithgow, T
- Abstract
Staphylococcus capitis is an opportunistic pathogen often implicated in bloodstream infections in the neonatal intensive care unit (NICU). This is assisted by its ability to form biofilms on indwelling central venous catheters (CVC), which are highly resistant to antibiotics and the immune system. We sought to understand the fundamentals of biofilm formation by S. capitis in the NICU, using seventeen clinical isolates including the endemic NRCS-A clone and assessing nine commercial and two modified polystyrene surfaces. S. capitis clinical isolates from the NICU initiated biofilm formation only in response to hyperosmotic conditions, followed by a developmental progression driven by icaADBC expression to establish mature biofilms, with polysaccharide being their major extracellular polymer substance (EPS) matrix component. Physicochemical features of the biomaterial surface, and in particular the level of the element oxygen present on the surface, significantly influenced biofilm development of S. capitis. A lack of highly oxidized carbon species on the surface prevented the immobilization of S. capitis EPS and the formation of mature biofilms. This information provides guidance in regard to the preparation of hyperosmolar total parenteral nutrition and the engineering of CVC surfaces that can minimize the risk of catheter-related bloodstream infections caused by S. capitis in the NICU.
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- 2020
6. Systems analysis. (Work at Height)
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Cameron, Dr. Iain, Duff, Dr. Roy, and Gillan, Gary
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Occupational health and safety -- Laws, regulations and rules ,Construction industry -- Safety and security measures ,Government regulation ,Business ,Business, international ,Health care industry - Abstract
In 2001/02 the UK construction industry suffered 79 fatal accidents, just under half of which were due to 'falls from height', with the other half largely attributable to 'falls from [...]
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- 2003
7. Developments for the Gwynt-y-Môr Offshore Wind Farm at Mostyn
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Cameron, Dr. Gordon, primary, Saadi, Rabah, additional, and Hughes, David W, additional
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- 2018
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8. Staff Ride Handbook For The Battle Of Perryville, 8 October 1862 [Illustrated Edition]
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Cameron, Dr. Robert S. and Cameron, Dr. Robert S.
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- Staff rides--Kentucky--Perryville, Perryville, Battle of, Perryville, Ky., 1862
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Illustrated with 9 figures and 11 maps of the campaign and engagements at Perryville.The battle of Perryville symbolized the high-water mark of the Confederacy in the western theater of operations. In Aug. 1862 General Braxton Bragg and Major General (MG) Edmund Kirby Smith led separate armies into Kentucky to wrest the state from the Union and install a Confederate governor. They initially met success and captured the state capital, simultaneously shifting the war in the west from northern Mississippi and Alabama to Kentucky. In response the North raised additional forces to protect Cincinnati and Louisville while MG Don Carlos Buell halted his offensive against Chattanooga and marched his Army of the Ohio back to Kentucky. On 8 Oct. 1862 Buell's army clashed with Bragg's at Perryville. The Confederates achieved a tactical success in a hard-fought engagement that generated more than 7,000 casualties. Of the regiments engaged, 10 suffered losses between 40 and 60 percent. However, outnumbered by three to one, Bragg's army could not sustain its victory and withdrew. Within days of the battle, all of the invading Southern forces retired from the state. Kentucky remained firmly in the Union and secure from Confederate invasion for the war's duration.Despite its importance to the course of the war in the west, Perryville does not benefit from the high visibility accorded the better-known Civil War sites such as Manassas, Gettysburg, Antietam, and Chickamauga. Although more than 70,000 Union and Confederate soldiers deployed in and around Perryville, understanding of the battle and its significance to the overall course of the war remains poor. For staff ride purposes this unfamiliarity can be a benefit. It forces the participants to study and think about the situation facing their Civil War counterparts without the preconceived notions that surround the more popular sites.
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- 2014
9. Identification of a Class of Protein ADP-Ribosylating Sirtuins in Microbial Pathogens
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Rack, JG, Morra, R, Barkauskaite, E, Kraehenbuehl, R, Ariza, A, Qu, Y, Ortmayer, M, Leidecker, O, Cameron, DR, Matic, I, Peleg, AY, Leys, D, Traven, A, and Ahel, I
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Models, Molecular ,Adenosine Diphosphate Ribose ,Staphylococcus aureus ,Protein Conformation ,Streptococcus pyogenes ,Lipoylation ,Cell Biology ,Crystallography, X-Ray ,Article ,Oxidative Stress ,HEK293 Cells ,Bacterial Proteins ,Genes, Bacterial ,Lactobacillales ,Catalytic Domain ,Host-Pathogen Interactions ,Operon ,Humans ,Sirtuins ,Molecular Biology ,Phylogeny - Abstract
Summary Sirtuins are an ancient family of NAD+-dependent deacylases connected with the regulation of fundamental cellular processes including metabolic homeostasis and genome integrity. We show the existence of a hitherto unrecognized class of sirtuins, found predominantly in microbial pathogens. In contrast to earlier described classes, these sirtuins exhibit robust protein ADP-ribosylation activity. In our model organisms, Staphylococcus aureus and Streptococcus pyogenes, the activity is dependent on prior lipoylation of the target protein and can be reversed by a sirtuin-associated macrodomain protein. Together, our data describe a sirtuin-dependent reversible protein ADP-ribosylation system and establish a crosstalk between lipoylation and mono-ADP-ribosylation. We propose that these posttranslational modifications modulate microbial virulence by regulating the response to host-derived reactive oxygen species., Graphical Abstract, Highlights • A class of sirtuins (SirTMs) is identified in microbial pathogens • SirTMs are linked to macrodomains and act as protein ADP-ribosyltransferases • Protein ADP-ribosylation by SirTMs is strictly lipoylation dependent and reversible • SirTMs modulate the response to oxidative stress, Oxidative stress has been recognized as a critical factor in human disease, aging, and the immune system function. Rack et al. report a structural and biochemical analysis of a sirtuin/macrodomain system modulating the oxidative stress response in pathogenic microorganisms via reversible protein ADP-ribosylation.
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- 2015
10. Considerations for the management of hazardous wastes in New Zealand
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Cameron, DR
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- 1985
11. Antibiotic regimen based on population analysis of residing persister cells eradicates Staphylococcus epidermidis biofilms
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Yang, S, Hay, ID, Cameron, DR, Speir, M, Cui, B, Su, F, Peleg, AY, Lithgow, T, Deighton, MA, Qu, Y, Yang, S, Hay, ID, Cameron, DR, Speir, M, Cui, B, Su, F, Peleg, AY, Lithgow, T, Deighton, MA, and Qu, Y
- Abstract
Biofilm formation is a major pathogenicity strategy of Staphylococcus epidermidis causing various medical-device infections. Persister cells have been implicated in treatment failure of such infections. We sought to profile bacterial subpopulations residing in S. epidermidis biofilms, and to establish persister-targeting treatment strategies to eradicate biofilms. Population analysis was performed by challenging single biofilm cells with antibiotics at increasing concentrations ranging from planktonic minimum bactericidal concentrations (MBCs) to biofilm MBCs (MBCbiofilm). Two populations of "persister cells" were observed: bacteria that survived antibiotics at MBCbiofilm for 24/48 hours were referred to as dormant cells; those selected with antibiotics at 8 X MICs for 3 hours (excluding dormant cells) were defined as tolerant-but-killable (TBK) cells. Antibiotic regimens targeting dormant cells were tested in vitro for their efficacies in eradicating persister cells and intact biofilms. This study confirmed that there are at least three subpopulations within a S. epidermidis biofilm: normal cells, dormant cells, and TBK cells. Biofilms comprise more TBK cells and dormant cells than their log-planktonic counterparts. Using antibiotic regimens targeting dormant cells, i.e. effective antibiotics at MBCbiofilm for an extended period, might eradicate S. epidermidis biofilms. Potential uses for this strategy are in antibiotic lock techniques and inhaled aerosolized antibiotics.
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- 2015
12. Phosphotyrosine-containing dipeptides as high-affinity ligands for the p56lck SH2 domain
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N. Moss, Llinaś-Brunet M, Rajashehar Betageri, Martin Poirier, Pierre L. Beaulieu, John R. Proudfoot, Jean Rancourt, Dominik Wernic, Gorys, Jean Gauthier, Susan Lukas, Mario G. Cardozo, Jean-Marie Ferland, Scott Jakes, Usha R. Patel, Cameron Dr, Ghiro Elise, and James Gillard
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chemistry.chemical_classification ,Models, Molecular ,Dipeptide ,Tetrapeptide ,Stereochemistry ,Peptide ,Dipeptides ,SH2 domain ,Ligands ,Binding, Competitive ,Amino acid ,Intracellular signal transduction ,src Homology Domains ,chemistry.chemical_compound ,Structure-Activity Relationship ,chemistry ,Lymphocyte Specific Protein Tyrosine Kinase p56(lck) ,Drug Discovery ,Molecular Medicine ,Isoleucine ,Enzyme Inhibitors ,Phosphotyrosine ,Proto-oncogene tyrosine-protein kinase Src - Abstract
Src homology-2 (SH2) domains are noncatalytic motifs containing approximately 100 amino acid residues that are involved in intracellular signal transduction. The phosphotyrosine-containing tetrapeptide Ac-pYEEI binds to the SH2 domain of p56lck (Lck) with an affinity of 0.1 microM. Starting from Ac-pYEEI, we have designed potent antagonists of the Lck SH2 domain which are reduced in peptidic character and in which the three carboxyl groups have been eliminated. The two C-terminal amino acids (EI) have been replaced by benzylamine derivatives and the pY + 1 glutamic acid has been substituted with leucine. The best C-terminal fragment identified, (S)-1-(4-isopropylphenyl)ethylamine, binds to the Lck SH2 domain better than the C-terminal dipeptide EI. Molecular modeling suggests that the substituents at the 4-position of the phenyl ring occupy the pY + 3 lipophilic pocket in the SH2 domain originally occupied by the isoleucine side chain. This new series of phosphotyrosine-containing dipeptides binds to the Lck SH2 domain with potencies comparable to that of tetrapeptide 1.
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- 1999
13. Daily low dose mifepristone has contraceptive potential by suppressing ovulation and menstruation: a double blind randomized control trial of 2 mg and 5 mg per day for 120 days. Brown A, Cheng L, Suiqing L, et al. J Clin Endocrinol Metab 2002; 87: 63-70
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Cameron, Dr Sharon, primary
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- 2002
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14. Older adults perceptions, experiences and anxieties with emerging technologies
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Cameron, Dr Don, primary, Marquis, Dr Ruth, additional, and Webster, Beverley, additional
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- 2001
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15. Potent β-Lactam Inhibitors of Human Cytomegalovirus Protease
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Yoakim, C, primary, Ogilvie, WW, additional, Cameron, DR, additional, Chabot, C, additional, Grand-Maître, C, additional, Guse, I, additional, Haché, B, additional, Kawai, S, additional, Naud, J, additional, O'Meara, JA, additional, Plante, R, additional, and Déziel, R, additional
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- 1998
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16. Book Review: Economics of the Family and Family Policies
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Cameron, Dr. S., primary
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- 1998
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17. Book ReviewsDetailed guide to research for the novice Nursing research: principles, process and issues K Parahoo, Macmillan, Basingstoke, 1997 Pp 403 Price £14.99 ISBN 0 333 699181Assessing the needs of the community Needs to Know: a guide to needs assessment for primary care Edited by Andrew Harris FT Healthcare, 1997 Pp 160 Price £21.50 ISBN 0 443 0 05569 6Protocol guide leaves out nurses' view The Minor Illness Manual Gina Johnson, Ian Hill-Smith and Chris Ellis Radcliffe Medical Press 1977 Pp 109 Price £12.95 ISBN 1 85775 285 6
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Cameron, Dr. Shona, primary, Willcox, Adrienne, additional, and Eveleigh, Marilyn, additional
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- 1997
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18. The Use of High Speed Selective Jet Electrodeposition of Gold for the Plating of Connectors
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Bocking, C., primary and Cameron, Dr. B., additional
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- 1994
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19. 'The Apparent Mid Zone Pneumatocele in the Intensive Care Patient'.
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CAMERON, DR. D. C.
- Abstract
ABSTRACT An apparent air-filled cyst is often seen projected through the right hilum in patients managed in an Intensive Care Unit. This may cause problems of interpretation but does not have the clinical significance of the developing acquired pneumatocoele. The radiographic appearances are discussed. SUMMARY The development of a cystic space projected through the hilum, more often on the right, has been observed frequently in patients in Intensive Care wards. These should not be interpreted as acquired pneumonatocoeles. The basis for this radiographic abnormality has been discussed. [ABSTRACT FROM AUTHOR]
- Published
- 1986
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20. Instant Expert: Solar cycles.
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Cameron, Dr. Robert
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- 2018
21. What's New in Optometry
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Cameron, Dr. Alex. S., primary
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- 1935
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22. TOUGH Grasses.
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CAMERON, DR. ART
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ORNAMENTAL grasses ,GARDENS ,LANDSCAPE gardening ,CALAMAGROSTIS ,SWITCHGRASS ,GRASSES - Abstract
The article suggests several ornamental grasses suited for landscape gardens. Two well known grasses recommended, include Calamagrostis x acutifolia 'Karl Foerster', more popularly known as feather reed grass and Panicum virgatum, also known as switch grass. Other grasses which are not as famous as these two, but may also provide exciting opportunities for landscape improvement, include Hakone grass, little blue stem and Indian grass.
- Published
- 2007
23. Model-based translation of results from in vitro to in vivo experiments for afabicin activity against Staphylococcus aureus.
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Saporta R, Nielsen EI, Menetrey A, Cameron DR, Nicolas-Metral V, and Friberg LE
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Background: Translation of experimental data on antibiotic activity typically relies on pharmacokinetic/pharmacodynamic (PK/PD) indices. Model-based approaches, considering the full antibiotic killing time course, could be an alternative., Objectives: To develop a mechanism-based modelling framework to assess the in vitro and in vivo activity of the FabI inhibitor antibiotic afabicin, and explore the ability of a model built on in vitro data to predict in vivo outcome., Methods: A PK/PD model was built to describe bacterial counts from 162 static in vitro time-kill curves evaluating the effect of afabicin desphosphono, the active moiety of the prodrug afabicin, against 21 Staphylococcus aureus strains. Combined with a mouse PK model, outcomes of afabicin doses of 0.011-190 mg/kg q6h against nine S. aureus strains in a murine thigh infection model were predicted, and thereafter refined by estimating PD parameters., Results: A sigmoid Emax model, with EC50 scaled by the MIC described the afabicin desphosphono killing in vitro. This model predicted, without parameter re-estimation, the in vivo bacterial counts at 24 h within a ±1 log margin for most dosing groups. When parameters were allowed to be estimated, EC50 was 38%-45% lower in vivo, compared with in vitro, within the studied MIC range., Conclusions: The developed PK/PD model described the time course of afabicin activity across experimental conditions and bacterial strains. This model showed translational capacity as parameters estimated on in vitro time-kill data could well predict the in vivo outcome for a wide variety of doses in a mouse thigh infection model., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)
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- 2024
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24. BET-inhibitor DYB-41 reduces pulmonary inflammation and local and systemic cytokine levels in LPS-induced acute respiratory distress syndrome: an experimental rodent study.
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Iten M, Gschwend C, Ostini A, Cameron DR, Goepfert C, Berger D, and Haenggi M
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Background: Acute respiratory distress syndrome (ARDS) is a form of respiratory failure stemming from various underlying conditions that ultimately lead to inflammation and lung fibrosis. Bromodomain and Extra-Terminal motif (BET) inhibitors are a class of medications that selectively bind to the bromodomains of BET motif proteins, effectively reducing inflammation. However, the use of BET inhibitors in ARDS treatment has not been previously investigated. In our study, we induced ARDS in rats using endotoxin and administered a BET inhibitor. We evaluated the outcomes by examining inflammation markers and lung histopathology., Results: Nine animals received treatment, while 12 served as controls. In the lung tissue of treated animals, we observed a significant reduction in TNFα levels (549 [149-977] pg/mg vs. 3010 [396-5529] pg/mg; p = 0.009) and IL-1β levels (447 [369-580] pg/mg vs. 662 [523-924] pg/mg; p = 0.012), although IL-6 and IL-10 levels showed no significant differences. In the blood, treated animals exhibited a reduced TNFα level (25 [25-424] pg/ml vs. 900 [285-1744] pg/ml, p = 0.016), but IL-1β levels were significantly higher (1254 [435-2474] pg/ml vs. 384 [213-907] pg/ml, p = 0.049). No differences were observed in IL-6 and IL-10 levels. There were no significant variations in lung tissue levels of TGF-β, SP-D, or RAGE. Histopathological analysis revealed substantial damage, with notably less perivascular edema (3 vs 2; p = 0.0046) and visually more inflammatory cells. However, two semi-quantitative histopathologic scoring systems did not indicate significant differences., Conclusions: These preliminary findings suggest a potential beneficial effect of BET inhibitors in the treatment of acute lung injury and ARDS. Further validation and replication of these results with a larger cohort of animals, in diverse models, and using different BET inhibitors are needed to explore their clinical implications., (© 2024. The Author(s).)
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- 2024
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25. Virulence attributes of successful methicillin-resistant Staphylococcus aureus lineages.
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Jiang J-H, Cameron DR, Nethercott C, Aires-de-Sousa M, and Peleg AY
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- Humans, Staphylococcus aureus, Virulence, Anti-Bacterial Agents, Exotoxins genetics, Exotoxins metabolism, Virulence Factors genetics, Methicillin-Resistant Staphylococcus aureus genetics, Community-Acquired Infections, Staphylococcal Infections drug therapy, Staphylococcal Infections epidemiology
- Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of severe and often fatal infections. MRSA epidemics have occurred in waves, whereby a previously successful lineage has been replaced by a more fit and better adapted lineage. Selection pressures in both hospital and community settings are not uniform across the globe, which has resulted in geographically distinct epidemiology. This review focuses on the mechanisms that trigger the establishment and maintenance of current, dominant MRSA lineages across the globe. While the important role of antibiotic resistance will be mentioned throughout, factors which influence the capacity of S. aureus to colonize and cause disease within a host will be the primary focus of this review. We show that while MRSA possesses a diverse arsenal of toxins including alpha-toxin, the success of a lineage involves more than just producing toxins that damage the host. Success is often attributed to the acquisition or loss of genetic elements involved in colonization and niche adaptation such as the arginine catabolic mobile element, as well as the activity of regulatory systems, and shift metabolism accordingly (e.g., the accessory genome regulator, agr ). Understanding exactly how specific MRSA clones cause prolonged epidemics may reveal targets for therapies, whereby both core (e.g., the alpha toxin) and acquired virulence factors (e.g., the Panton-Valentine leukocidin) may be nullified using anti-virulence strategies., Competing Interests: The authors declare no conflict of interest.
- Published
- 2023
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26. Natural climate solutions provide robust carbon mitigation capacity under future climate change scenarios.
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Marvin DC, Sleeter BM, Cameron DR, Nelson E, and Plantinga AJ
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Natural climate solutions (NCS) are recognized as an important tool for governments to reduce greenhouse gas emissions and remove atmospheric carbon dioxide. Using California as a globally relevant reference, we evaluate the magnitude of biological climate mitigation potential from NCS starting in 2020 under four climate change scenarios. By mid-century NCS implementation leads to a large increase in net carbon stored, flipping the state from a net source to a net sink in two scenarios. Forest and conservation land management strategies make up 85% of all NCS emissions reductions by 2050, with agricultural strategies accounting for the remaining 15%. The most severe climate change impacts on ecosystem carbon materialize in the latter half of the century with three scenarios resulting in California ecosystems becoming a net source of carbon emissions under a baseline trajectory. However, NCS provide a strong attenuating effect, reducing land carbon emissions 41-54% by 2100 with total costs of deployment of 752-777 million USD annually through 2050. Rapid implementation of a portfolio of NCS interventions provides long-term investment in protecting ecosystem carbon in the face of climate change driven disturbances. This open-source, spatially-explicit framework can help evaluate risks to NCS carbon storage stability, implementation costs, and overall mitigation potential for NCS at jurisdictional scales., (© 2023. The Author(s).)
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- 2023
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27. Dynamics of bacterial pathogens at the driveline exit site in patients with ventricular assist devices: A prospective, observational, single-center cohort study.
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Pitton M, Valente LG, Oberhaensli S, Casanova C, Sendi P, Schnegg B, Jakob SM, Cameron DR, Que YA, and Fürholz M
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- Humans, Cohort Studies, Prospective Studies, Retrospective Studies, Bacteria, Prosthesis-Related Infections etiology, Heart-Assist Devices adverse effects, Heart Failure
- Abstract
Background: Driveline infections (DLIs) at the exit site are frequent in patients with left ventricular assist devices (LVADs). The dynamics from colonization to infection are yet to be investigated. We combined systematic swabbing at the driveline exit site and genomic analyses to study the dynamics of bacterial pathogens and get insights into DLIs pathogenesis., Methods: A prospective, observational, single-center cohort study at the University Hospital of Bern, Switzerland was performed. Patients with LVAD were systematically swabbed at the driveline exit site between June 2019 and December 2021, irrespective of signs and symptoms of DLI. Bacterial isolates were identified and a subset was whole-genome sequenced., Results: Fifty-three patients were screened, of which 45 (84.9%) were included in the final population. Bacterial colonization at the driveline exit site without manifestation of DLI was frequent and observed in 17 patients (37.8%). Twenty-two patients (48.9%) developed at least one DLI episode over the study period. Incidence of DLIs reached 2.3 cases per 1000 LVAD days. The majority of the organisms cultivated from exit sites were Staphylococcus species. Genome analysis revealed that bacteria persisted at the driveline exit site over time. In four patients, transition from colonization to clinical DLI was observed., Conclusions: Our study is the first to address bacterial colonization in the LVAD-DLI setting. We observed that bacterial colonization at the driveline exit site was a frequent phenomenon, and in a few cases, it preceded clinically relevant infections. We also provided acquisition of hospital-acquired multidrug-resistant bacteria and the transmission of pathogens between patients., (Copyright © 2023 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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28. Evaluation of the microbiota-sparing properties of the anti-staphylococcal antibiotic afabicin.
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Nowakowska J, Cameron DR, De Martino A, Kühn J, Le Fresne-Languille S, Leuillet S, Amouzou Y, Wittke F, Carton T, Le Vacon F, Chaves RL, Nicolas-Metral V, and Vuagniaux G
- Subjects
- Humans, Mice, Animals, Clindamycin pharmacology, Moxifloxacin therapeutic use, Linezolid pharmacology, Staphylococcus, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Microbiota
- Abstract
Background: Antibiotic use is associated with collateral damage to the healthy microbiota. Afabicin is a first-in-class prodrug inhibitor of the FabI enzyme that, when converted to the pharmacologically active agent afabicin desphosphono, demonstrates a staphylococcal-specific spectrum of activity. An expected benefit of highly targeted antibiotics such as afabicin is microbiome preservation., Objectives: To compare the effects of oral treatment with afabicin and standard-of-care antibiotics upon the murine gut microbiota, and to assess the effects of oral afabicin treatment on the human gut microbiota., Methods: Gut microbiota effects of a 10 day oral course of afabicin treatment were monitored in mice and compared with clindamycin, linezolid and moxifloxacin at human-equivalent dose levels using 16S rDNA sequencing. Further, the gut microbiota of healthy volunteers was longitudinally assessed across 20 days of oral treatment with afabicin 240 mg twice daily., Results: Afabicin treatment did not significantly alter gut microbiota diversity (Shannon H index) or richness (rarefied Chao1) in mice. Only limited changes to taxonomic abundances were observed in afabicin-treated animals. In contrast, clindamycin, linezolid and moxifloxacin each caused extensive dysbiosis in the murine model. In humans, afabicin treatment was not associated with alterations in Shannon H or rarefied Chao1 indices, nor relative taxonomic abundances, supporting the findings from the animal model., Conclusions: Oral treatment with afabicin is associated with preservation of the gut microbiota in mice and healthy subjects., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)
- Published
- 2023
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29. Ten-year retrospective cohort analysis of ventricular assist device infections.
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Spano G, Buffle E, Walti LN, Mihalj M, Cameron DR, Martinelli M, Fürholz M, Que YA, Hayward C, Reineke D, Hunziker L, and Schnegg B
- Subjects
- Male, Humans, Female, Middle Aged, Retrospective Studies, Cohort Studies, Risk Factors, Treatment Outcome, Heart-Assist Devices adverse effects, Heart-Assist Devices microbiology, Diabetes Mellitus, Heart Failure surgery, Heart Failure etiology
- Abstract
Background: The number of patients treated by ventricular assist devices (VAD) and the duration of VAD treatment is increasing. One of the main complications in terms of morbidity and mortality for VAD patients are microbial infections. With this study, we aimed to investigate the epidemiology and microbiological characteristics of infections occurring in a VAD population to identify modifiable factors., Methods: We retrospectively analyzed patient characteristics, treatments and outcomes of VAD-specific/related infections. All patients implanted in our institution with a continuous flow VAD between January 2009 and January 2019 were included. Risk factors for VAD infection were assessed using simple and multiple linear regressions., Results: Of the 104 patients screened, 99 were included in the analysis, the majority of which were men (78%). At implantation, the mean age was 56 years and the median time on VAD support was 541 days. The overall infection rate per year per patient was 1.4. Forty-seven patients (60%) suffered from VAD-specific/related infection. Half of all infection episodes occurred in the first 4 months but the proportion of VAD-specific/related infection was higher after the first 4 months (74% of all infection). Using regression models, no patient specific risk factors were associated with VAD-specific/related infections., Conclusion: No predictive factors for infection during VAD support were identified in this study. By extension, diabetes, renal insufficiency, age or high BMI are not sufficient to deny a patient access to ventricular support., (© 2022 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)
- Published
- 2023
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30. A resilient and connected network of sites to sustain biodiversity under a changing climate.
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Anderson MG, Clark M, Olivero AP, Barnett AR, Hall KR, Cornett MW, Ahlering M, Schindel M, Unnasch B, Schloss C, and Cameron DR
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- Humans, United States, Biodiversity, Climate Change, Movement, Ecosystem, Conservation of Natural Resources
- Abstract
Motivated by declines in biodiversity exacerbated by climate change, we identified a network of conservation sites designed to provide resilient habitat for species, while supporting dynamic shifts in ranges and changes in ecosystem composition. Our 12-y study involved 289 scientists in 14 study regions across the conterminous United States (CONUS), and our intent was to support local-, regional-, and national-scale conservation decisions. To ensure that the network represented all species and ecosystems, we stratified CONUS into 68 ecoregions, and, within each, we comprehensively mapped the geophysical settings associated with current ecosystem and species distributions. To identify sites most resilient to climate change, we identified the portion of each geophysical setting with the most topoclimate variability (high landscape diversity) likely to be accessible to dispersers (high local connectedness). These "resilient sites" were overlaid with conservation priority maps from 104 independent assessments to indicate current value in supporting recognized biodiversity. To identify key connectivity areas for sustaining species movement in response to climate change, we codeveloped a fine-scale representation of human modification and ran a circuit-theory-based analysis that emphasized movement potential along geographic climate gradients. Integrating areas with high values for two or more factors, we identified a representative, resilient, and connected network of biodiverse lands covering 35% of CONUS. Because the network connects climatic gradients across 250,000 biodiversity elements and multiple resilient examples of all geophysical settings in every ecoregion, it could form the spatial foundation for targeted land protection and other conservation strategies to sustain a diverse, dynamic, and adaptive world.
- Published
- 2023
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31. Parallel Evolution of Pseudomonas aeruginosa during a Prolonged ICU-Infection Outbreak.
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Cameron DR, Pitton M, Oberhaensli S, Schlegel K, Prod'hom G, Blanc DS, Jakob SM, and Que YA
- Subjects
- Humans, Anti-Bacterial Agents pharmacology, Carbapenems, Mutation, Disease Outbreaks, Microbial Sensitivity Tests, Porins genetics, Pseudomonas aeruginosa genetics, Pseudomonas Infections epidemiology
- Abstract
Most knowledge about Pseudomonas aeruginosa pathoadaptation is derived from studies on airway colonization in cystic fibrosis; little is known about adaptation in acute settings. P. aeruginosa frequently affects burned patients and the burn wound niche has distinct properties that likely influence pathoadaptation. This study aimed to genetically and phenotypically characterize P. aeruginosa isolates collected during an outbreak of infection in a burn intensive care unit (ICU). Sequencing reads from 58 isolates of ST1076 P. aeruginosa taken from 23 patients were independently mapped to a complete reference genome for the lineage (H25338); genetic differences were identified and were used to define the population structure. Comparative genomic analysis at single-nucleotide resolution identified pathoadaptive genes that evolved multiple, independent mutations. Three key phenotypic assays (growth performance, motility, carbapenem resistance) were performed to complement the genetic analysis for 47 unique isolates. Population structure for the ST1076 lineage revealed 11 evolutionary sublineages. Fifteen pathoadaptive genes evolved mutations in at least two sublineages. The most prominent functional classes affected were transcription/two-component regulatory systems, and chemotaxis/motility and attachment. The most frequently mutated gene was oprD , which codes for outer membrane porin involved in uptake of carbapenems. Reduced growth performance and motility were found to be adaptive phenotypic traits, as was high level of carbapenem resistance, which correlated with higher carbapenem consumption during the outbreak. Multiple prominent linages evolved each of the three traits in parallel providing evidence that they afford a fitness advantage for P. aeruginosa in the context of human burn infection. IMPORTANCE Pseudomonas aeruginosa is a Gram-negative pathogen causing infections in acutely burned patients. The precise mechanisms required for the establishment of infection in the burn setting, and adaptive traits underpinning prolonged outbreaks are not known. We have assessed genotypic data from 58 independent P. aeruginosa isolates taken from a single lineage that was responsible for an outbreak of infection in a burn ICU that lasted for almost 2.5 years and affected 23 patients. We identified a core set of 15 genes that we predict to control pathoadaptive traits in the burn infection based on the frequency with which independent mutations evolved. We combined the genotypic data with phenotypic data (growth performance, motility, antibiotic resistance) and clinical data (antibiotic consumption) to identify adaptive phenotypes that emerged in parallel. High-level carbapenem resistance evolved rapidly, and frequently, in response to high clinical demand for this antibiotic class during the outbreak.
- Published
- 2022
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32. Accuracy, realism and general applicability of European forest models.
- Author
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Mahnken M, Cailleret M, Collalti A, Trotta C, Biondo C, D'Andrea E, Dalmonech D, Marano G, Mäkelä A, Minunno F, Peltoniemi M, Trotsiuk V, Nadal-Sala D, Sabaté S, Vallet P, Aussenac R, Cameron DR, Bohn FJ, Grote R, Augustynczik ALD, Yousefpour R, Huber N, Bugmann H, Merganičová K, Merganic J, Valent P, Lasch-Born P, Hartig F, Vega Del Valle ID, Volkholz J, Gutsch M, Matteucci G, Krejza J, Ibrom A, Meesenburg H, Rötzer T, van der Maaten-Theunissen M, van der Maaten E, and Reyer CPO
- Subjects
- Carbon, Temperature, Water, Carbon Cycle, Climate Change
- Abstract
Forest models are instrumental for understanding and projecting the impact of climate change on forests. A considerable number of forest models have been developed in the last decades. However, few systematic and comprehensive model comparisons have been performed in Europe that combine an evaluation of modelled carbon and water fluxes and forest structure. We evaluate 13 widely used, state-of-the-art, stand-scale forest models against field measurements of forest structure and eddy-covariance data of carbon and water fluxes over multiple decades across an environmental gradient at nine typical European forest stands. We test the models' performance in three dimensions: accuracy of local predictions (agreement of modelled and observed annual data), realism of environmental responses (agreement of modelled and observed responses of daily gross primary productivity to temperature, radiation and vapour pressure deficit) and general applicability (proportion of European tree species covered). We find that multiple models are available that excel according to our three dimensions of model performance. For the accuracy of local predictions, variables related to forest structure have lower random and systematic errors than annual carbon and water flux variables. Moreover, the multi-model ensemble mean provided overall more realistic daily productivity responses to environmental drivers across all sites than any single individual model. The general applicability of the models is high, as almost all models are currently able to cover Europe's common tree species. We show that forest models complement each other in their response to environmental drivers and that there are several cases in which individual models outperform the model ensemble. Our framework provides a first step to capturing essential differences between forest models that go beyond the most commonly used accuracy of predictions. Overall, this study provides a point of reference for future model work aimed at predicting climate impacts and supporting climate mitigation and adaptation measures in forests., (© 2022 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)
- Published
- 2022
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33. Efficacy of phage therapy in preclinical models of bacterial infection: a systematic review and meta-analysis.
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Gómez-Ochoa SA, Pitton M, Valente LG, Sosa Vesga CD, Largo J, Quiroga-Centeno AC, Hernández Vargas JA, Trujillo-Cáceres SJ, Muka T, Cameron DR, and Que YA
- Subjects
- Humans, Anti-Bacterial Agents therapeutic use, Phage Therapy, Bacterial Infections therapy
- Abstract
Background: Antimicrobial resistance of bacterial pathogens is an increasing clinical problem and alternative approaches to antibiotic chemotherapy are needed. One of these approaches is the use of lytic bacterial viruses known as phage therapy. We aimed to assess the efficacy of phage therapy in preclinical animal models of bacterial infection., Methods: In this systematic review and meta-analysis, MEDLINE/Ovid, Embase/Ovid, CINAHL/EbscoHOST, Web of Science/Wiley, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Google Scholar were searched from inception to Sept 30, 2021. Studies assessing phage efficacy in animal models were included. Only studies that assessed the efficacy of phage therapy in treating established bacterial infections in terms of survival and bacterial abundance or density were included. Studies reporting only in-vitro or ex-vivo results and those with incomplete information were excluded. Risk-of-bias assessment was performed using the Systematic Review Centre for Laboratory Animal Experimentation tool. The main endpoints were animal survival and tissue bacterial burden, which were reported using pooled odds ratios (ORs) and mean differences with random-effects models. The I
2 measure and its 95% CI were also calculated. This study is registered with PROSPERO, CRD42022311309., Findings: Of the 5084 references screened, 124 studies fulfilled the selection criteria. Risk of bias was high for 70 (56%) of the 124 included studies; therefore, only studies classified as having a low-to-moderate risk of bias were considered for quantitative data synthesis (n=32). Phage therapy was associated with significantly improved survival at 24 h in systemic infection models (OR 0·08 [95% CI 0·03 to 0·20]; I2 =55% [95% CI 8 to 77]), skin infection (OR 0·08 [0·04 to 0·19]; I2 = 0% [0 to 79]), and pneumonia models (OR 0·13 [0·06 to 0·31]; I2 =0% [0 to 68]) when compared with placebo. Animals with skin infections (mean difference -2·66 [95% CI -3·17 to -2·16]; I2 = 95% [90 to 96]) and those with pneumonia (mean difference -3·35 [-6·00 to -0·69]; I2 = 99% [98 to 99]) treated with phage therapy had significantly lower tissue bacterial loads at 5 ± 2 days of follow-up compared with placebo., Interpretation: Phage therapy significantly improved animal survival and reduced organ bacterial loads compared with placebo in preclinical animal models. However, high heterogeneity was observed in some comparisons. More evidence is needed to identify the factors influencing phage therapy performance to improve future clinical application., Funding: Swiss National Foundation and Swiss Heart Foundation., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2022
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34. Mutation to ispA Produces Stable Small-Colony Variants of Pseudomonas aeruginosa That Have Enhanced Aminoglycoside Resistance.
- Author
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Pitton M, Oberhaensli S, Appiah F, Pagani JL, Fournier A, Jakob SM, Que YA, and Cameron DR
- Subjects
- Anti-Bacterial Agents pharmacology, Drug Resistance, Microbial, Humans, Mutation, Aminoglycosides pharmacology, Bacterial Proteins genetics, Pseudomonas aeruginosa genetics
- Abstract
Pseudomonas aeruginosa is a major pathogen in burn wound infections. We present one of the first reports of small-colony variant (SCV) emergence of P. aeruginosa, taken from a patient under aminoglycosides for a persistent burn wound infection. We confirm the causative role of a single ispA mutation in SCV emergence and increased aminoglycoside resistance. IspA is involved in the synthesis of ubiquinone, providing a possible link between electron transport and SCV formation in P. aeruginosa.
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- 2022
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35. Development and early diagnosis of critical illness myopathy in COVID-19 associated acute respiratory distress syndrome.
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Rodriguez B, Branca M, Gutt-Will M, Roth M, Söll N, Nansoz S, Cameron DR, Tankisi H, Tan SV, Bostock H, Raabe A, Schefold JC, Jakob SM, and Z'Graggen WJ
- Subjects
- Adult, Critical Illness epidemiology, Early Diagnosis, Humans, Middle Aged, Pandemics, COVID-19 complications, COVID-19 diagnosis, Muscular Diseases diagnosis, Muscular Diseases epidemiology, Muscular Diseases etiology, Polyneuropathies diagnosis, Polyneuropathies epidemiology, Polyneuropathies etiology, Respiratory Distress Syndrome
- Abstract
Background: The COVID-19 pandemic has greatly increased the incidence and clinical importance of critical illness myopathy (CIM), because it is one of the most common complications of modern intensive care medicine. Current diagnostic criteria only allow diagnosis of CIM at an advanced stage, so that patients are at risk of being overlooked, especially in early stages. To determine the frequency of CIM and to assess a recently proposed tool for early diagnosis, we have followed a cohort of COVID-19 patients with acute respiratory distress syndrome and compared the time course of muscle excitability measurements with the definite diagnosis of CIM., Methods: Adult COVID-19 patients admitted to the Intensive Care Unit of the University Hospital Bern, Switzerland requiring mechanical ventilation were recruited and examined on Days 1, 2, 5, and 10 post-intubation. Clinical examination, muscle excitability measurements, medication record, and laboratory analyses were performed on all study visits, and additionally nerve conduction studies, electromyography and muscle biopsy on Day 10. Muscle excitability data were compared with a cohort of 31 age-matched healthy subjects. Diagnosis of definite CIM was made according to the current guidelines and was based on patient history, results of clinical and electrophysiological examinations as well as muscle biopsy., Results: Complete data were available in 31 out of 44 recruited patients (mean [SD] age, 62.4 [9.8] years). Of these, 17 (55%) developed CIM. Muscle excitability measurements on Day 10 discriminated between patients who developed CIM and those who did not, with a diagnostic precision of 90% (AUC 0.908; 95% CI 0.799-1.000; sensitivity 1.000; specificity 0.714). On Days 1 and 2, muscle excitability parameters also discriminated between the two groups with 73% (AUC 0.734; 95% CI 0.550-0.919; sensitivity 0.562; specificity 0.857) and 82% (AUC 0.820; CI 0.652-0.903; sensitivity 0.750; specificity 0.923) diagnostic precision, respectively. All critically ill COVID-19 patients showed signs of muscle membrane depolarization compared with healthy subjects, but in patients who developed CIM muscle membrane depolarization on Days 1, 2 and 10 was more pronounced than in patients who did not develop CIM., Conclusions: This study reports a 55% prevalence of definite CIM in critically ill COVID-19 patients. Furthermore, the results confirm that muscle excitability measurements may serve as an alternative method for CIM diagnosis and support its use as a tool for early diagnosis and monitoring the development of CIM., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)
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- 2022
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36. Efficacy assessment of a novel endolysin PlyAZ3aT for the treatment of ceftriaxone-resistant pneumococcal meningitis in an infant rat model.
- Author
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Valente LG, Le ND, Pitton M, Chiffi G, Grandgirard D, Jakob SM, Cameron DR, Resch G, Que YA, and Leib SL
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- Animals, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Ceftriaxone pharmacology, Ceftriaxone therapeutic use, Endopeptidases, Random Allocation, Rats, Rats, Wistar, Streptococcus pneumoniae, Vancomycin pharmacology, Meningitis, Pneumococcal microbiology
- Abstract
Background: Treatment failure in pneumococcal meningitis due to antibiotic resistance is an increasing clinical challenge and alternatives to antibiotics warrant investigation. Phage-derived endolysins efficiently kill gram-positive bacteria including multi-drug resistant strains, making them attractive therapeutic candidates. The current study assessed the therapeutic potential of the novel endolysin PlyAZ3aT in an infant rat model of ceftriaxone-resistant pneumococcal meningitis., Methods: Efficacy of PlyAZ3aT was assessed in a randomized, blinded and controlled experimental study in infant Wistar rats. Meningitis was induced by intracisternal infection with 5 x 107 CFU/ml of a ceftriaxone-resistant clinical strain of S. pneumoniae, serotype 19A. Seventeen hours post infection (hpi), animals were randomized into 3 treatment groups and received either (i) placebo (phosphate buffered saline [PBS], n = 8), (ii) 50 mg/kg vancomycin (n = 10) or (iii) 400 mg/kg PlyAZ3aT (n = 8) via intraperitoneal injection. Treatments were repeated after 12 h. Survival at 42 hpi was the primary outcome; bacterial loads in cerebrospinal fluid (CSF) and blood were secondary outcomes. Additionally, pharmacokinetics of PlyAZ3aT in serum and CSF was assessed., Results: PlyAZ3aT did not improve survival compared to PBS, while survival for vancomycin treated animals was 70% which is a significant improvement when compared to PBS or PlyAZ3aT (p<0.05 each). PlyAZ3aT was not able to control the infection, reflected by the inability to reduce bacterial loads in the CSF, whereas Vancomycin sterilized the CSF and within 25 h. Pharmacokinetic studies indicated that PlyAZ3aT did not cross the blood brain barrier (BBB). In support, PlyAZ3aT showed a peak concentration of 785 μg/ml in serum 2 h after intraperitoneal injection but could not be detected in CSF., Conclusion: In experimental pneumococcal meningitis, PlyAZ3aT failed to cure the infection due to an inability to reach the CSF. Optimization of the galenic formulation e.g. using liposomes might enable crossing of the BBB and improve treatment efficacy., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2022
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37. Benefits of Aerosolized Phages for the Treatment of Pneumonia Due to Methicillin-Resistant Staphylococcus aureus: An Experimental Study in Rats.
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Prazak J, Valente LG, Iten M, Federer L, Grandgirard D, Soto S, Resch G, Leib SL, Jakob SM, Haenggi M, Cameron DR, and Que YA
- Subjects
- Animals, Linezolid therapeutic use, Rats, Bacteriophages, Methicillin-Resistant Staphylococcus aureus, Pneumonia, Staphylococcal microbiology, Pneumonia, Ventilator-Associated drug therapy
- Abstract
Background: The optimal method for delivering phages in the context of ventilator-associated pneumonia (VAP) is unknown. In the current study, we assessed the utility of aerosolized phages (aerophages) for experimental methicillin-resistant Staphylococcus aureus (MRSA) pneumonia., Methods: Rats were ventilated for 4 hours before induction of pneumonia. Animals received one of the following: (1) aerophages; (2) intravenous (IV) phages; (3) a combination of IV and aerophages; (4) IV linezolid; or (5) a combination of IV linezolid and aerophages. Phages were administered at 2, 12, 24, 48, and 72 hours, and linezolid was administered at 2, 12, 24, 36, 48, 60, and 72 hours. The primary outcome was survival at 96 hours. Secondary outcomes were bacterial and phage counts in tissues and histopathological scoring of the lungs., Results: Aerophages and IV phages each rescued 50% of animals from severe MRSA pneumonia (P < .01 compared with placebo controls). The combination of aerophages and IV phages rescued 91% of animals, which was higher than either monotherapy (P < .05). Standard-of-care antibiotic linezolid rescued 38% of animals. However, linezolid and aerophages did not synergize in this setting (55% survival)., Conclusions: Aerosolized phage therapy showed potential for the treatment of MRSA pneumonia in an experimental animal model and warrants further investigation for application in humans., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)
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- 2022
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38. Increasing taxonomic diversity and spatial resolution clarifies opportunities for protecting US imperiled species.
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Hamilton H, Smyth RL, Young BE, Howard TG, Tracey C, Breyer S, Cameron DR, Chazal A, Conley AK, Frye C, and Schloss C
- Subjects
- Animals, Biodiversity, Birds, Ecosystem, Mammals, Butterflies, Conservation of Natural Resources
- Abstract
Continental- and regional-scale assessments of gaps in protected area networks typically use relatively coarse range maps for well documented species groups, creating uncertainty about the fate of unexamined biodiversity and providing insufficient guidance for land managers. By building habitat suitability models for a taxonomically diverse group of 2216 imperiled plants and animals, we revealed comprehensive and detailed protection opportunities in the conterminous United States. Summing protection-weighted range-size rarity (PWRSR, the product of the percent of modeled habitat outside of protected areas and the inverse of modeled habitat extent) uncovered novel patterns of biodiversity importance. Concentrations of unprotected imperiled species in places such as the northern Sierra Nevada, central and northern Arizona, the Rocky Mountains of Utah and Colorado, southeastern Texas, southwestern Arkansas, and Florida's Lake Wales Ridge have rarely if ever been featured in continental- and regional-scale analyses. Inclusion of diverse taxa (vertebrates, freshwater mussels, crayfishes, bumble bees, butterflies, skippers, and vascular plants) partially drove these new patterns. When analyses were restricted to groups typically included in previous studies (birds, mammals, and amphibians), up to 53% of imperiled species in other groups were left out. The finer resolution of modeled inputs (990 m) also resulted in a more geographically dispersed pattern. For example, 90% of the human population of the conterminous United States lives within 50 km of modeled habitat for one or more species with high PWRSR scores. Over one-half of the habitat for 818 species occurs within federally lands managed for biodiversity protection; an additional 360 species have over one-half of their modeled habitat on federal multiple use land. Freshwater animals occur in places with poorer landscape condition but with less exposure to climate change than other groups, suggesting that habitat restoration is an important conservation strategy for these species. The results provide fine-scale, taxonomically diverse inputs for local and regional priority-setting and show that although protection efforts are still widely needed on private lands, notable gains can be achieved by increasing protection status on selected federal lands., (© 2022 The Authors. Ecological Applications published by Wiley Periodicals LLC on behalf of The Ecological Society of America.)
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- 2022
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39. "No-regrets" pathways for navigating climate change: planning for connectivity with land use, topography, and climate.
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Schloss CA, Cameron DR, McRae BH, Theobald DM, and Jones A
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- Animals, Biodiversity, Ecosystem, Plants, Climate Change, Conservation of Natural Resources
- Abstract
As both plant and animal species shift their ranges in response to a changing climate, maintaining connectivity between present habitat and suitable habitat in the future will become increasingly important to ensure lasting protection for biodiversity. Because the temporal period commensurate with planning for mid-century change is multi-generational for most species, connectivity designed to facilitate climate adaptation requires pathways with 'stepping-stones' between current and future habitat. These areas should have habitats suitable not only for dispersal, but for all aspects of species lifecycles. We integrated present-day land use, topographic diversity, and projections of shifting climate regimes into a single connectivity modeling approach to identify pathways for mid-century shifts in species ranges. Using Omniscape we identified climate linkages, or areas important for climate change-driven movement, as the areas with more current flow than would be expected in the absence of climate considerations. This approach identified connectivity potential between natural lands in the present climate and natural lands with future analogous climate following topo-climatically diverse routes. We then translated the model output into a strategic framework to improve interpretation and to facilitate a more direct connection with conservation action. Across modified landscapes, pathways important to climate-driven movement were highly coincident with the last remaining present-day linkages, reinforcing their importance. Across unfragmented lands, the presence of climate-adapted pathways helped inform the prioritization of conservation actions in areas where multiple connectivity options still exist. Many climate linkages follow major watercourses along elevational gradients, highlighting the importance of protecting or managing for these natural linear pathways that provide movement routes for climate adaptation. By integrating enduring landscape features with climate projections and present-day land uses, our approach reveals "no-regrets" pathways to plan for a connected landscape in an uncertain future., (© 2021 The Nature Conservancy. Ecological Applications published by Wiley Periodicals LLC on behalf of The Ecological Society of America.)
- Published
- 2022
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40. Searching for synergy: combining systemic daptomycin treatment with localised phage therapy for the treatment of experimental pneumonia due to MRSA.
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Valente LG, Federer L, Iten M, Grandgirard D, Leib SL, Jakob SM, Haenggi M, Cameron DR, Que YA, and Prazak J
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- Animals, Anti-Bacterial Agents therapeutic use, Humans, Rats, Bacteriophages, Daptomycin, Methicillin-Resistant Staphylococcus aureus, Phage Therapy, Pneumonia, Ventilator-Associated, Staphylococcal Infections drug therapy
- Abstract
Objective: Bacteriophages (or phages) are viruses which infect and lyse bacteria. The therapeutic use of phages (phage therapy) has regained attention in the last decades as an alternative strategy to treat infections caused by antimicrobial-resistant bacteria. In clinical settings it is most likely that phages are administered adjunct to antibiotics. For successful phage therapy it is therefore crucial to investigate different phage-antibiotic combinations in vivo. This study aimed to elucidate the combinatorial effects of systemic daptomycin and nebulised bacteriophages for the treatment of experimental pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA)., Results: Using a rat model of ventilator-associated pneumonia caused by MRSA, the simultaneous application of intravenous daptomycin and nebulised phages was not superior to aerophage therapy alone at improving animal survival (55% vs. 50%), or reducing bacterial burdens in the lungs, or spleen. Thus, this combination does not seem to be of benefit for use in patients with MRSA pneumonia., (© 2021. The Author(s).)
- Published
- 2021
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41. Is myopathy part of long-Covid?
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Rodriguez B, Nansoz S, Cameron DR, and Z'Graggen WJ
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- Adult, Female, Humans, COVID-19 complications, Muscular Diseases etiology
- Abstract
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
- Published
- 2021
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42. Towards robust statistical inference for complex computer models.
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Oberpriller J, Cameron DR, Dietze MC, and Hartig F
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- Bayes Theorem, Computer Simulation, Forecasting, Uncertainty, Ecosystem, Models, Statistical
- Abstract
Ecologists increasingly rely on complex computer simulations to forecast ecological systems. To make such forecasts precise, uncertainties in model parameters and structure must be reduced and correctly propagated to model outputs. Naively using standard statistical techniques for this task, however, can lead to bias and underestimation of uncertainties in parameters and predictions. Here, we explain why these problems occur and propose a framework for robust inference with complex computer simulations. After having identified that model error is more consequential in complex computer simulations, due to their more pronounced nonlinearity and interconnectedness, we discuss as possible solutions data rebalancing and adding bias corrections on model outputs or processes during or after the calibration procedure. We illustrate the methods in a case study, using a dynamic vegetation model. We conclude that developing better methods for robust inference of complex computer simulations is vital for generating reliable predictions of ecosystem responses., (© 2021 The Authors. Ecology Letters published by John Wiley & Sons Ltd.)
- Published
- 2021
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43. Isolation and characterization of bacteriophages from the human skin microbiome that infect Staphylococcus epidermidis .
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Valente LG, Pitton M, Fürholz M, Oberhaensli S, Bruggmann R, Leib SL, Jakob SM, Resch G, Que YA, and Cameron DR
- Abstract
Phage therapy might be a useful approach for the treatment of nosocomial infections; however, only few lytic phages suitable for this application are available for the opportunistic pathogen, Staphylococcus epidermidis . In the current study, we developed an efficient method to isolate bacteriophages present within the human skin microbiome, by using niche-specific S. epidermidis as the host for phage propagation. Staphylococcus epidermidis was identified on the forehead of 92% of human subjects tested. These isolates were then used to propagate phages present in the same skin sample. Plaques were observable on bacterial lawns in 46% of the cases where S. epidermidis was isolated. A total of eight phage genomes were genetically characterized, including the previously described phage 456. A total of six phage sequences were unique, and spanned each of the major staphylococcal phage families; Siphoviridae ( n = 3), Podoviridae ( n = 1) and Myoviridae ( n = 2). One of the myoviruses (vB_SepM_BE06) was identified on the skin of three different humans. Comparative analysis identified novel genes including a putative N-acetylmuramoyl-L-alanine amidase gene. The host-range of each unique phage was characterized using a panel of diverse staphylococcal strains ( n = 78). None of the newly isolated phages infected more than 52% of the S. epidermidis strains tested ( n = 44), and non- S. epidermidis strains where rarely infected, highlighting the narrow host-range of the phages. One of the phages (vB_SepM_BE04) was capable of killing staphylococcal cells within biofilms formed on polyurethane catheters. Uncovering a richer diversity of available phages will likely improve our understanding of S. epidermidis -phage interactions, which will be important for future therapy., Competing Interests: None declared., (© The Author(s) 2021. Published by Oxford University Press on behalf of FEMS.)
- Published
- 2021
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44. Progress and Pitfalls of Bacteriophage Therapy in Critical Care: A Concise Definitive Review.
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Valente L, Prazak J, Que YA, and Cameron DR
- Abstract
Objective: Bacterial infections caused by antibiotic-resistant pathogens are a major problem for patients requiring critical care. An approach to combat resistance is the use of bacterial viruses known as "phage therapy." This review provides a brief "clinicians guide" to phage biology and discusses recent applications in the context of common infections encountered in ICUs., Data Sources: Research articles were sourced from PubMed using search term combinations of "bacteriophages" or "phage therapy" with either "lung," "pneumonia," "bloodstream," "abdominal," "urinary tract," or "burn wound.", Study Selection: Preclinical trials using animal models, case studies detailing compassionate use of phage therapy in humans, and randomized controlled trials were included., Data Extraction: We systematically extracted: 1) the infection setting, 2) the causative bacterial pathogen and its antibiotic resistance profile, 3) the nature of the phage therapeutic and how it was administered, 4) outcomes of the therapy, and 5) adverse events., Data Synthesis: Phage therapy for the treatment of experimental infections in animal models and in cases of compassionate use in humans has been associated with largely positive outcomes. These findings, however, have failed to translate into positive patient outcomes in the limited number of randomized controlled trails that have been performed to date., Conclusions: Widespread clinical implementation of phage therapy depends on success in randomized controlled trials. Additional translational and reverse translational studies aimed at overcoming phage resistance, exploiting phage-antibiotic synergies, and optimizing phage administration will likely improve the design and outcome of future trials., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)
- Published
- 2021
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45. Bacterial persisters in long-term infection: Emergence and fitness in a complex host environment.
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Bartell JA, Cameron DR, Mojsoska B, Haagensen JAJ, Pressler T, Sommer LM, Lewis K, Molin S, and Johansen HK
- Subjects
- Adult, Female, Genetic Fitness, Humans, Male, Pseudomonas Infections genetics, Pseudomonas aeruginosa genetics, Cystic Fibrosis microbiology, Host-Pathogen Interactions physiology, Pseudomonas Infections microbiology
- Abstract
Despite intensive antibiotic treatment, Pseudomonas aeruginosa often persists in the airways of cystic fibrosis (CF) patients for decades, and can do so without antibiotic resistance development. Using high-throughput screening assays of bacterial survival after treatment with high concentrations of ciprofloxacin, we have determined the prevalence of persisters in a large patient cohort using 460 longitudinal isolates of P. aeruginosa from 39 CF patients. Isolates were classed as high persister variants (Hip) if they regrew following antibiotic treatment in at least 75% of the experimental replicates. Strain genomic data, isolate phenotyping, and patient treatment records were integrated in a lineage-based analysis of persister formation and clinical impact. In total, 19% of the isolates were classified as Hip and Hip emergence increased over lineage colonization time within 22 Hip+ patients. Most Hip+ lineages produced multiple Hip isolates, but few Hip+ lineages were dominated by Hip. While we observed no strong signal of adaptive genetic convergence within Hip isolates, they generally emerged in parallel or following the development of ciprofloxacin resistance and slowed growth. Transient lineages were majority Hip-, while strains that persisted over a clinically diagnosed 'eradication' period were majority Hip+. Patients received indistinguishable treatment regimens before Hip emergence, but Hip+ patients overall were treated significantly more than Hip- patients, signaling repeated treatment failure. When subjected to in vivo-similar antibiotic dosing, a Hip isolate survived better than a non-Hip in a structured biofilm environment. In sum, the Hip phenotype appears to substantially contribute to long-term establishment of a lineage in the CF lung environment. Our results argue against the existence of a single dominant molecular mechanism underlying bacterial antibiotic persistence. We instead show that many routes, both phenotypic and genetic, are available for persister formation and consequent increases in strain fitness and treatment failure in CF airways., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2020
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46. Defense mechanisms to increasing back pressure for hepatic oxygen transport and venous return in porcine fecal peritonitis.
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Liu S, do Amaral Campos PPZ, Casoni D, Berger D, Kohler A, Bloch A, Bervini D, Setzer F, Cameron DR, Z'Graggen W, Hana A, Langer R, Corrêa TD, Beldi G, Takala J, and Jakob SM
- Subjects
- Animals, Feces, Hemodynamics, Hepatic Artery, Kidney metabolism, Oxygen blood, Pressure, Regional Blood Flow, Resuscitation, Swine, Central Venous Pressure, Liver metabolism, Oxygen Consumption, Peritonitis metabolism
- Abstract
High central venous pressure (CVP) acutely decreases venous return. How this affects hepatic oxygen transport in sepsis remains unclear. The aim of this study was to evaluate the effects of repeated increases in CVP via standard nursing procedures (NPs) on hepato-splanchnic and renal oxygen transport in a prolonged porcine sepsis model. Twenty anesthetized and mechanically ventilated pigs with regional hemodynamics monitored were randomized to fecal peritonitis or controls ( n = 10 pigs/group). Resuscitation was started after 8 h of observation and continued for 3 days. NPs were performed at baseline and 8 h, 32 h, 56 h, and 72 h after resuscitation started. NPs increased CVP by 4-7 mmHg in both groups. In controls, this was associated with less decrease in hepatic arterial (Q
ha ; 62 ± 70 mL/min) than portal venous flow (Qpv ; 364 ± 151 mL/min). Portal venous oxygen content and hepatic O2 delivery (Do2 ) and consumption (V̇o2 ) decreased by 11 ± 6 mL/dL and 0.9 ± 0.3 and 0.4 ± 0.3 mL·min-1 ·kg-1 , respectively. In septic animals, hepatic Do2 decreased more in response to increasing CVP (1.5 ± 0.9 mL·min-1 ·kg-1 ), which was attributable to a larger fall in both Qha (88 ± 66 ml/min) and portal O2 content (14 ± 10 mL/dL, all P < 0.05). This resulted in numerically lower hepatic V̇o2 since O2 extraction did not increase significantly. In control conditions, a smaller decrease in Qha compared with Qpv helped to limit the reduction in hepatic V̇o2 in response to acute CVP increase. In sepsis, the contribution of Qha to maintain hepatic Do2 was reduced, which jeopardized hepatic V̇o2 further. Renal arterial flow was similarly affected by CVP increase as Qha . NEW & NOTEWORTHY Sepsis impairs intrinsic mechanisms to attenuate effects of increasing back pressure on hepatic oxygen transport.- Published
- 2020
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47. Nebulized Bacteriophages for Prophylaxis of Experimental Ventilator-Associated Pneumonia Due to Methicillin-Resistant Staphylococcus aureus.
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Prazak J, Valente L, Iten M, Grandgirard D, Leib SL, Jakob SM, Haenggi M, Que YA, and Cameron DR
- Subjects
- Aerosols, Animals, Male, Nebulizers and Vaporizers virology, Rats, Rats, Wistar, Methicillin-Resistant Staphylococcus aureus, Phage Therapy methods, Pneumonia, Staphylococcal prevention & control, Pneumonia, Ventilator-Associated prevention & control
- Abstract
Objectives: There is a need for alternative strategies to combat and prevent antibiotic-resistant bacterial infections. Here, we assessed the potential for bacteriophage prophylaxis in the context of experimental ventilator-associated pneumonia due to methicillin-resistant Staphylococcus aureus in rats., Design: Nebulized phages (aerophages) were delivered to the lungs of rats using a modified vibrating mesh aerosol drug delivery system. Animals were intubated and ventilated for 4 hours, at which point they were infected with methicillin-resistant S. aureus strain AW7 via the endotracheal tube, extubated, and then monitored for 96 hours., Setting: Ventilator-associated pneumonia., Subjects: Male Wistar rats., Interventions: A single application of aerophages prior to ventilation at one of two concentrations (~1010 plaque forming units/mL or ~1011 plaque forming units/mL)., Measurements and Main Results: 1) Animal survival at 96 hours, 2) enumeration of bacteria and phages in the lungs and spleen, and 3) lung tissue histopathology. Animals that received aerophages prior to ventilation and methicillin-resistant S. aureus challenge showed a higher survival rate compared with untreated controls (60% for animals that received 3 × 10 plaque forming units; 70% for animals that received 3 × 10 plaque forming units; 0% for controls; p < 0.01 for each treatment versus untreated). Surviving animals that received aerophage prophylaxis had fewer methicillin-resistant S. aureus in the lungs compared with untreated control animals that succumbed to pneumonia (1.6 × 10 colony forming units/g vs 8.0 × 10; p < 0.01)., Conclusions: Prophylactically administered nebulized bacteriophages reduced lung bacterial burdens and improved survival of methicillin-resistant S. aureus infected rats, underscoring its potential in the context of ventilator-associated pneumonia.
- Published
- 2020
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48. Hyperosmotic Infusion and Oxidized Surfaces Are Essential for Biofilm Formation of Staphylococcus capitis From the Neonatal Intensive Care Unit.
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Qu Y, Li Y, Cameron DR, Easton CD, Zhu X, Zhu M, Salwiczek M, Muir BW, Thissen H, Daley A, Forsythe JS, Peleg AY, and Lithgow T
- Abstract
Staphylococcus capitis is an opportunistic pathogen often implicated in bloodstream infections in the neonatal intensive care unit (NICU). This is assisted by its ability to form biofilms on indwelling central venous catheters (CVC), which are highly resistant to antibiotics and the immune system. We sought to understand the fundamentals of biofilm formation by S. capitis in the NICU, using seventeen clinical isolates including the endemic NRCS-A clone and assessing nine commercial and two modified polystyrene surfaces. S. capitis clinical isolates from the NICU initiated biofilm formation only in response to hyperosmotic conditions, followed by a developmental progression driven by icaADBC expression to establish mature biofilms, with polysaccharide being their major extracellular polymer substance (EPS) matrix component. Physicochemical features of the biomaterial surface, and in particular the level of the element oxygen present on the surface, significantly influenced biofilm development of S. capitis . A lack of highly oxidized carbon species on the surface prevented the immobilization of S. capitis EPS and the formation of mature biofilms. This information provides guidance in regard to the preparation of hyperosmolar total parenteral nutrition and the engineering of CVC surfaces that can minimize the risk of catheter-related bloodstream infections caused by S. capitis in the NICU., (Copyright © 2020 Qu, Li, Cameron, Easton, Zhu, Zhu, Salwiczek, Muir, Thissen, Daley, Forsythe, Peleg and Lithgow.)
- Published
- 2020
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49. Bacteriophages Improve Outcomes in Experimental Staphylococcus aureus Ventilator-associated Pneumonia.
- Author
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Prazak J, Iten M, Cameron DR, Save J, Grandgirard D, Resch G, Goepfert C, Leib SL, Takala J, Jakob SM, Que YA, and Haenggi M
- Subjects
- Animals, Anti-Bacterial Agents therapeutic use, Bacteriophages, Disease Models, Animal, Male, Rats, Rats, Wistar, Staphylococcal Infections microbiology, Teicoplanin therapeutic use, Methicillin-Resistant Staphylococcus aureus, Phage Therapy, Pneumonia, Ventilator-Associated microbiology, Pneumonia, Ventilator-Associated therapy, Staphylococcal Infections therapy
- Abstract
Rationale: Infections caused by multidrug-resistant bacteria are a major clinical challenge. Phage therapy is a promising alternative antibacterial strategy. Objectives: To evaluate the efficacy of intravenous phage therapy for the treatment of ventilator-associated pneumonia due to methicillin-resistant Staphylococcus aureus in rats. Methods: In a randomized, blinded, controlled experimental study, we compared intravenous teicoplanin (3 mg/kg, n = 12), a cocktail of four phages (2-3 × 10
9 plaque-forming units/ml of 2003, 2002, 3A, and K; n = 12), and a combination of both ( n = 11) given 2, 12, and 24 hours after induction of pneumonia, and then once daily for 4 days. The primary outcome was survival at Day 4. Secondary outcomes were bacterial and phage densities in lungs and spleen, histopathological scoring of infection within the lungs, and inflammatory biomarkers in blood. Measurements and Main Results: Treatment with either phages or teicoplanin increased survival from 0% to 58% and 50%, respectively ( P < 0.005). The combination of phages and antibiotics did not further improve outcomes (45% survival). Animal survival correlated with reduced bacterial burdens in the lung (1.2 × 106 cfu/g of tissue for survivors vs. 1.2 × 109 cfu/g for nonsurviving animals; P < 0.0001), as well as improved histopathological outcomes. Phage multiplication within the lung occurred during treatment. IL-1β increased in all treatment groups over the course of therapy. Conclusions: Phage therapy was as effective as teicoplanin in improving survival and decreasing bacterial load within the lungs of rats infected with methicillin-resistant S. aureus . Combining antibiotics with phage therapy did not further improve outcomes.- Published
- 2019
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50. Draft Genome Sequence of Methicillin-Resistant Staphylococcus aureus Strain AW7, Isolated from a Patient with Bacteremia.
- Author
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Cameron DR, Ramette A, Prazak J, Entenza J, Haenggi M, Que YA, and Resch G
- Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) strain AW7 is a commonly used challenge strain in experimental models of MRSA infection. Here, we report its draft genome sequence., (Copyright © 2019 Cameron et al.)
- Published
- 2019
- Full Text
- View/download PDF
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