Managing emerging mutagenicity risks: Late stage mutagenic impurity control within the atovaquone second generation synthesis.

The mutagenic-impurity control strategy for a second generation manufacturing route to the non-mutagenic antipneumocystic agent atovaquone (2-((1R,4R)-4-(4-chlorophenyl)cyclohexyl)-3-hydroxynaphthalene-1,4-dione) 1 is described. Preliminary assessment highlighted multiple materials of concern which were largely discharged either through returning a negative bacterial mutagenicity assay or through confidence that the impurity would be purged during the downstream processing from when it was first introduced. Additional genotoxicity testing highlighted two materials of concern where initial assessment suggested that testing for these impurities at trace levels within the drug substance would be required. Following a thorough review of process purging detail, spiking and purging experimentation, and an understanding of the process parameters to which they were exposed an ICH M7 Option 4 approach could be justified for their control. The development of two 1H NMR spectroscopy methods for measurement of these impurities is also described as well as a proposed summary table for describing the underlying rationale for ICH M7 control rationales to regulators. This manuscript demonstrates that process purging of potential mutagenic impurities can be realised even when they are introduced in the later stages of a process and highlights the importance of scientific understanding rather than relying on a stage-counting approach.

Functional Hand-Based Splint in the Treatment of Metacarpal Fractures.

Background: Post-treatment stiffness remains a significant hurdle following treatment for displaced or minimally displaced metacarpal fractures. Treatment goals should focus on a stable and acceptable reduction, minimal patient morbidity, and optimal mobility. Methods: A retrospective review of all non-operative metacarpal fractures over a five-month period at a tertiary center hand clinic treated with a hand-based splint were reviewed for radiologic and clinical stability. The splint allowed metacarpophalngeal joint, interphalangeal joint, and radiocarpal joint motion. Data collected included age, handedness, type and location of fracture, occupation, and ability to continue working. Radiologic images were reviewed by a radiologist not otherwise involved in patient care. Results: Thirty-three patients were reviewed with a total of 39 fractures of the second, third, fourth, and fifth metacarpals. Nine patients had nondominant hand fractures while 24 were dominant hand injuries. Twenty out of 24 patients employed pre-injury were able to continue working without missing any days. Three patients were lost to the final follow-up. The average splint duration was 24 days. Twenty-seven of 30 patients showed no change in alignment from start of splinting to end, while three showed some change but remained within non-operative criteria. Conclusion: A hand-based functional splint for metacarpal fractures allows for excellent maintenance of fracture reduction, early or immediate return to pre-injury activities, low patient morbidity, and maintains functional motion throughout treatment. It can be applied to any non-operative fracture of the second through the fifth metacarpal.

Contexte: La raideur post-traitement reste un obstacle significatif après traitement des fractures métacarpiennes déplacées ou peu déplacées. Les objectifs thérapeutiques doivent se concentrer sur une réduction stable et acceptable, une morbidité minimale pour le patient et une mobilité optimale. Méthodes: La stabilité radiologique et clinique de toutes les fractures métacarpiennes non opérées sur une période de cinq mois dans un centre tertiaire de traitement de la main avec une attelle basée sur la main a fait l'objet d'une analyse rétrospective. L'attelle permettait le mouvement de l'articulation métacarpophalangienne, de l'articulation interphalangienne et de l'articulation radiocarpienne. Les données ollectées ont inclus l'âge, le côté de la main dominante, le type et l'emplacement de la fracture, la profession et l'aptitude à poursuivre le travail. Les images radiographiques ont été analysées par un radiologiste qui n'était pas impliqué dans les soins aux patients. Résultats: Trente-trois patients ont été inclus dans l'analyse avec un total de 39 fractures des 2e, 3e, 4e et 5e métacarpiens. Neuf patients avaient des fractures de la main non dominante et 24 patients avaient des blessures de la main dominante. Parmi les 24 patients à l'emploi avant la blessure, 20 ont pu continuer à travailler sans manquer un seul jour. Trois patients ont été perdus de vue au suivi final. La durée moyenne du port de l'attelle a été de vingt-quatre jours. Sur 30 patients, 27 n'ont eu aucune modification de l'alignement entre le moment de la pose de l'attelle et son retrait, tandis qu'un changement a été observé chez trois patients, sans pour autant répondre à des critères d'indication chirurgicale. Conclusion: Une attelle fonctionnelle basée sur la main pour les fractures métacarpiennes permet une excellente conservation de la réduction de la fracture et un retour précoce ou immédiat aux activités habituelles avant la blessure, une faible morbidité pour les patients et le maintien d'une mobilité fonctionnelle tout au long du traitement. Cette technique est applicable à toute fracture non chirurgicale du 2e au 5e métacarpien.

Successful same day discharge after immediate post-mastectomy alloplastic breast reconstruction: A single tertiary centre retrospective audit.

BACKGROUND: Immediate Post-Mastectomy Alloplastic Breast Reconstruction (IPMABR) traditionally requires a post-operative overnight stay. Recent initiatives have identified same day discharge as a safe option. METHODS: A retrospective audit of all cases at a tertiary breast cancer centre was performed. Patients received surgery at a day care facility or regional hospital (RH). Unplanned admission was defined as any patient unable to be discharged or any patient returning to the emergency room within the first 24 h. Planned admission cases had a history of BMI >40, obstructive sleep apnoea or previous anaesthetic complications. Data were collected on planned same day discharge, unplanned admission and planned admission cases. Factors differentiating the groups were identified and variables predicting unplanned admission were determined. RESULTS: A total of 785 patients received IPMABR over a 5-year period of which 743 had satisfactory data sets for review. Greater than 96% of patients receiving care at the day care facility were successfully discharged. The success rate for same day discharge at the RH was 65%. We determined that the greatest variables determining successful planned discharge were shorter surgical time (67 min; SD 6 min; p<.01), shorter PACU time (130 min; SD 21 min; p<.01) and surgical institution (p<.01). This difference between institutions was significant when all other variables (age, co-morbidities, unilateral/bilateral and BMI) were controlled, indicating a strong institutional bias. There was no difference between groups in complication rates (infection, dehiscence, seroma and haematoma). CONCLUSION: Same day discharge following IPMABR is safe and greatly reduces resource use. It is imperative that members of the perioperative team understand the validity and benefits of the programme to ensure success and reduce unplanned admissions.

Factors Influencing Plastic Surgeons When Selecting New Colleagues.

INTRODUCTION: As plastic surgeons are continuing to form larger groups, it is essential to select candidates who will contribute to a positive work environment. This article shows which traits may be the most valuable when selecting candidates and in which ways a selection committee may want to focus their search. METHODS: For the study, the Canadian Society of Plastic Surgeons' members answered a survey containing questions about demographics, the factors which influence the selection process, and their hiring experiences. Responses were separated and compared in groups based on gender, practice type, group size, and years practising. Significance was established if P < .05 using the χ2 test. RESULTS: The most and least important factors regarding hiring a new group member were established. Statistically significant results were obtained between several different factors, including hiring a non-Canadian, the importance of the candidate's professional reputation, the number of publications by the candidate, and the presence or absence of program director letters. A majority (54%) of society members regret having hired a candidate, with the vast majority of these (75%) indicating personality and work ethic issues as opposite to professional skills as the uncomplimentary feature. CONCLUSION: This study has identified the key features which influence hiring new candidates. The need to develop a more efficient hiring process has been identified and has highlighted the difficulty faced by Canadian plastic surgery groups when recruiting new members.

Precision atomic beam density characterization by diode laser absorption spectroscopy.

We provide experimental and theoretical details of a simple technique to determine absolute line-of-sight integrated atomic beam densities based on resonant laser absorption. In our experiments, a thermal lithium beam is chopped on and off while the frequency of a laser crossing the beam at right angles is scanned slowly across the resonance transition. A lock-in amplifier detects the laser absorption signal at the chop frequency from which the atomic density is determined. The accuracy of our experimental method is confirmed using the related technique of wavelength modulation spectroscopy. For beams which absorb of order 1% of the incident laser light, our measurements allow the beam density to be determined to an accuracy better than 5% and with a precision of 3% on a time scale of order 1 s. Fractional absorptions of order 10-5 are detectable on a one-minute time scale when we employ a double laser beam technique which limits laser intensity noise. For a lithium beam with a thickness of 9 mm, we have measured atomic densities as low as 5 × 104 atoms cm-3. The simplicity of our technique and the details we provide should allow our method to be easily implemented in most atomic or molecular beam apparatuses.

Millimeter-wave achromatic half-wave plate.

We have constructed an achromatic half-wave plate (AHWP) suitable for the millimeter wavelength band. The AHWP was made from a stack of three sapphire a-cut birefringent plates with the opticalaxes of the middle plate rotated by 50.5 deg with respect to the aligned axes of the other plates. The measured modulation efficiency of the AHWP at 110 GHz was 96 +/- 1.5%. In contrast, the modulation efficiency of a single sapphire plate of the same thickness was 43 +/- 4%. Both results are in close agreement with theoretical predictions. The modulation efficiency of the AHWP was constant as a function of incidence angles between 0 and 15 deg. We discuss design parameters of an AHWP in the context of astrophysical broadband polarimetry at the millimeter wavelength band.