Effectiveness of nirmatrelvir/ritonavir (Paxlovid®) in preventing hospitalisation and death among COVID-19 patients: a prospective cohort study.

INTRODUCTION: Previous trials and real-world studies have shown that nirmatrelvir/ritonavir (Paxlovid®) reduces hospitalisation and deaths in symptomatic, high-risk, nonsevere COVID-19 patients. However, there was a scarcity of data on its effectiveness in the local setting. This study aimed to determine the effectiveness of Paxlovid® in reducing hospitalisation and mortality among COVID-19 patients and to identify the types of adverse events that occur after taking Paxlovid®. MATERIALS AND METHODS: A two-arm prospective cohort study was conducted among adult patients with COVID-19 categories 2 and 3 treated with Paxlovid® and a matched control group. A standard risk-stratified scoring system was used to establish Paxlovid® eligibility. All patients who were prescribed Paxlovid® and took at least one dose of Paxlovid® were included in the study. The control patients were selected from a centralised COVID-19 patient registry and matched based on age, gender and COVID-19 stage severity. RESULTS: A total of 552 subjects were included in the study and evenly allocated to the treatment and control groups. There was no statistically significant difference in 28-day hospitalisation after diagnosis [Paxlovid®: 26 (9.4%), Control: 34 (12.3%), OR: 0.74; 95%CI, 0.43-1.27; p=0.274] or all-cause death [Paxlovid®: 2 (0.7%), Control: 3 (1.1%), OR 1.51; 95%CI, 0.25-9.09; p=0.999]. There was no significant reduction in hospitalisation duration, intensive care unit admission events or supplementary oxygen requirement in the treatment arm. Ethnicity, COVID-19 severity at diagnosis, comorbidities and vaccination status were predictors of hospitalisation events. CONCLUSION: In this two-arm study, Paxlovid® did not significantly lower the incidence of hospitalisation, all-cause death and the need for supplemental oxygen. Adverse effects were frequent but not severe. Paxlovid® efficacy varied across settings and populations, warranting further real-world investigations.

Human Immunodeficiency Virus-infected men who have sex with men with syphilis: A 5-year multicentre study in Malaysia.

OBJECTIVES: High rates of syphilis have been reported worldwide among men who have sex with men (MSM). This study aims to describe the clinical pattern and treatment response of syphilis among human immunodeficiency virus (HIV)-infected MSM in Malaysia. METHODS: This is a retrospective study on all HIV-infected MSM with syphilis between 2011 and 2015. Data was collected from case notes in five centres namely Hospital Kuala Lumpur, Hospital Sultanah Bahiyah, Hospital Umum Sarawak, University of Malaya Medical Centre and Hospital Sungai Buloh. RESULTS: A total of 294 HIV seropositive MSM with the median age of 29 years (range 16-66) were confirmed to have syphilis. Nearly half (47.6%) were in the age group of 20-29 years. About a quarter (24.1%) was previously infected with syphilis. Eighty-three patients (28.2%) had other concomitant sexually transmitted infection with genital warts being the most frequently reported (17%). The number of patients with early and late syphilis in our cohort were almost equal. The median pre-treatment non-treponemal antibody titre (VDRL or RPR) for early syphilis (1:64) was significantly higher than for late syphilis (1:8) (p<0.0001). The median CD4 count and the number of patients with CD4 <200/µl in early syphilis were comparable to late syphilis. Nearly four-fifth (78.9%) received benzathine-penicillin only, 5.8% doxycycline, 1.4% Cpenicillin, 1% procaine penicillin, and 12.4% a combination of the above medications. About 44% received treatment and were lost to follow-up. Among those who completed 1 -year follow-up after treatment, 72.3% responded to treatment (serological non-reactive - 18.2%, four-fold drop in titre - 10.9%; serofast - 43.6%), 8.5% failed treatment and 17% had re-infection. Excluding those who were re-infected, lost to follow-up and died, the rates of treatment failure were 12.1% and 8.8% for early and late syphilis respectively (p=0.582). CONCLUSION: The most common stage of syphilis among MSM with HIV was latent syphilis. Overall, about 8.5% failed treatment at 1-year follow-up.

Interaction of nanodiamonds with bacteria.

Nanocarbons come in many forms and among their applications is the engineering of biocompatible and antibacterial materials. Studies have shown that diamond nanoparticles might have the interesting combination of both properties: they are highly biocompatible, while surprisingly reducing bacterial viability or growth at the same time. In this article, we consider for the first time the interaction of milled HPHT nanodiamonds with bacteria. These nanoparticles are capable of hosting nitrogen-vacancy (NV) centers, which provide stable fluorescence with potential use in sensing applications. An initial study was performed to assess the interaction of partially oxidized monocrystalline nanodiamonds with Gram positive S. aureus ATCC 12600 and Gram negative E. coli ATCC 8739. It was shown that for S. aureus ATCC 12600, the presence of these nanodiamonds leads to a sharp reduction of colony forming ability under optimal conditions. A different effect was observed on Gram negative E. coli ATCC 8739, where no significant adverse effects of ND presence was observed. The mode of interaction was further studied by electron microscopy and confocal microscopy. The effects of NDs on S. aureus viability were found to depend on many factors, including the concentration and size of nanoparticles, the suspension medium and incubation time.

Shape and crystallographic orientation of nanodiamonds for quantum sensing.

Nanodiamonds with dimensions down to a few tens of nanometers containing nitrogen-vacancy (NV) color centers have revealed their potential as powerful and versatile quantum sensors with a unique combination of spatial resolution and sensitivity. The NV centers allow transducing physical properties, such as strain, temperature, and electric or magnetic field, to an optical transition that can be detected in the single photon range. For example, this makes it possible to sense a single electron spin or a few nuclear spins by detecting their magnetic resonance. The location and orientation of these defects with respect to the diamond surface play a crucial role in interpreting the data and predicting their sensitivities. Despite its relevance, the geometry of these nanodiamonds has never been thoroughly investigated. Without accurate data, spherical models have been applied to interpret or predict results in the past. With the use of High Resolution Transmission Electron Microscopy (HR-TEM), Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM), we investigated nanodiamonds with an average hydrodynamic diameter of 25 nm (the most common type for quantum sensing) and found a flake-like geometry, with 23.2 nm and 4.5 nm being the average lateral and vertical dimensions. We have also found evidence for a preferred crystallographic orientation of the main facet in the (110) direction. Furthermore, we discuss the consequences of this difference in geometry on diamond-based applications. Shape not only influences the creation efficiency of nitrogen-vacancy centers and their quantum coherence properties (and thus sensing performance), but also the optical properties of the nanodiamonds, their interaction with living cells, and their surface chemistry.

Early relapse post autologous transplant is a stronger predictor of survival compared with pretreatment patient factors in the novel agent era: analysis of the Singapore Multiple Myeloma Working Group.

The clinical outcome of multiple myeloma is heterogeneous. Both the depth of response to induction and transplant as well as early relapse within a year are correlated with survival, but it is unclear which factor is most relevant in Southeast Asian patients with multiple myeloma. We retrospectively analyzed outcomes of 215 patients who were treated with upfront autologous transplant in Singapore between 2000 and 2014. In patients who received novel agent (NA)-based induction, achieving only partial response (PR) post-induction was associated with poorer OS (HR 1.95, P=0.047) and PFS (HR 2.9, P<0.001), while achieving only PR post-transplant was strongly correlated with both OS (HR 3.3, P=0.001) and PFS (HR 7.6, P<0.001), compared with patients who achieved very good partial response (VGPR) or better. Early relapse was detected in 18% of all patients, although nearly half had initially achieved VGPR or better post-transplant. Early relapse after NA-based induction led to significantly shorter OS (median 22 months vs not reached, P<0.001), and was strongly associated with OS (HR 13.7, P<0.001). The impact of suboptimal post-transplant response and early relapse on survival may be more important than pretransplant factors, such as International Staging System or cytogenetics, and should be considered in risk stratification systems to rationalize therapy.

Incidence and predictors of new-onset constipation during acute hospitalisation after stroke.

OBJECTIVES: We investigated new-onset constipation in patients with stroke compared with orthopaedic conditions and explored the predictors associated with constipation during acute hospitalisation. METHODS: This was a prospective matched cohort study of 110 patients comparing stroke patients (n = 55) with orthopaedic patients (n = 55) admitted to a large tertiary acute hospital. Both cohorts were matched by age and sex. The incidence of new-onset constipation which occurred during a patient's acute hospitalisation was determined. Demographics, comorbidity, clinical factors, laboratory parameters and medications were evaluated as possible predictors of constipation. RESULTS: The incidence of new-onset constipation was high for both stroke (33%) and orthopaedic patients (27%; p = 0.66). Seven stroke patients (39%) and four orthopaedic patients (27%) developed their first onset of constipation on day 2 of admission. Mobility gains (RR 0.741, p < 0.001) and the use of prophylactic laxatives (RR 0.331, p < 0.01) had a protective effect against constipation. Bedpan use (RR 2.058, p < 0.05) and longer length of stay (RR 1.032, p < 0.05) increased the risk of developing new-onset constipation. CONCLUSIONS: New-onset constipation is common among patients admitted for stroke and orthopaedic conditions during acute hospitalisation. The early occurrence, on day 2 of admission, calls for prompt preventive intervention for constipation.

Substance P and vasoactive intestinal peptide are reduced in right transverse colon in pediatric slow-transit constipation.

BACKGROUND: Slow-transit constipation (STC) is recognized in children but the etiology is unknown. Abnormalities in substance P (SP), vasoactive intestinal peptide (VIP) and nitric oxide (NO) have been implicated. The density of nerve fibers in circular muscle containing these transmitters was examined in colon from children with STC and compared to other pediatric and adult samples. METHODS: Fluorescence immunohistochemistry using antibodies to NO synthase (NOS), VIP and SP was performed on colonic biopsies (transverse and sigmoid colon) from 33 adults with colorectal cancer, 11 children with normal colonic transit and anorectal retention (NAR) and 51 with chronic constipation and slow motility in the proximal colon (STC). The percentage area of nerve fibers in circular muscle containing each transmitter was quantified in confocal images. KEY RESULTS: In colon circular muscle, the percentage area of nerve fibers containing NOS > VIP > SP (6 : 2 : 1). Pediatric groups had a higher density of nerve fibers than adults. In pediatric samples, there were no regional differences in NOS and VIP, while SP nerve fiber density was higher in sigmoid than proximal colon. STC children had lower SP and VIP nerve fiber density in the proximal colon than NAR children. Twenty-three percent of STC children had low SP nerve fiber density. CONCLUSIONS & INFERENCES: There are age-related reductions in nerve fiber density in human colon circular muscle. NOS and VIP do not show regional variations, while SP nerve fiber density is higher in distal colon. 1/3 of pediatric STC patients have low SP or VIP nerve fiber density in proximal colon.

Decrease in nerve fibre density in human sigmoid colon circular muscle occurs with growth but not aging.

BACKGROUND: Studies in animals suggest that enteric neurons decrease in density or number with increasing age. Neurons containing nitric oxide (NO), vasoactive intestinal peptide (VIP) and Substance P (SP) have been implicated. In human large intestine, NO-utilizing neurons decrease during childhood or early adulthood but it is not known if the innervation of the muscle changes. This study examined the density of nerve fibres containing these transmitters in sigmoid colon circular muscle from children and adults. METHODS: Fluorescence immunohistochemistry using antibodies to neuronal NO synthase (nNOS), VIP and SP was performed on sigmoid colon from 18 adults with colorectal cancer, two children with familial adenomatous polyposis, and normal colon from nine children with Hirschsprung's disease. The percentage area of immunoreactive (IR) nerve fibres containing each transmitter in circular muscle was quantified in confocal images. KEY RESULTS: In the adult sigmoid colon circular muscle, the percentage area of nerve fibres containing nNOS>VIP>SP (6 : 2 : 1). Paediatric groups had significantly higher percentage area of nerve fibres containing nNOS, VIP or SP-IR than adults, with the decrease in nerve fibre density occurring from birth to 30 years. Circular muscle thickness increased between 12 and 30 years. Total nerve fibre area remained constant, while the muscle increased in thickness. CONCLUSIONS & INFERENCES: In human sigmoid colon circular muscle, there are reductions in nNOS-, VIP- and SP-IR nerve fibre density with growth from newborn to late adolescence but little further change with aging. The reduction in nerve density is due to an increase in circular muscle thickness rather than a loss of nerve fibres.

Disruption of adeB gene has a greater effect on resistance to meropenems than adeA gene in Acinetobacter spp. isolated from University Malaya Medical Centre.

INTRODUCTION: The AdeABC pump of Acinetobacter spp. confers resistance to various antibiotic classes. This pump is composed of the AdeA, AdeB, and AdeC proteins where AdeB is a member of the resistance-nodulation-division efflux pump superfamily. The adeA, adeB, and adeC genes are contiguous and adjacent to adeS and adeR, which are transcribed in the opposite direction and which specify proteins homologous to sensors and regulators of two-component systems, respectively. In this study, an attempt is made to elucidate the role of the AdeABC efflux pump in carbapenem resistance in Acinetobacter spp. METHODS: 39 carbapenem-resistant clinical isolates of Acinetobacter spp. were used. Minimum inhibitory concentrations were evaluated using the agar dilution method according to Clinical and Laboratory Standards Institute standards. The presence of carbapenem hydrolysing oxacillinases and AdeABC efflux pump genes were determined by PCR amplification. Subsequently, each gene was inactivated by plasmid insertion in order to study the contribution of these genes in developing antibiotic resistance and the resulting mutants were tested for their antimicrobial susceptibilities. RESULTS: Among the multidrug-resistant strains, 36 strains had all the three (A, B, C) genes detected, while the remaining three strains had one or two of the genes detected. Inactivation of these individual genes showed decreased antimicrobial susceptibility indicating its contribution towards the development of antimicrobial resistance. CONCLUSION: The presence of AdeABC multidrug efflux pump plays a major role in the development of antimicrobial resistance in Acinetobacter spp. The presence of either one or an interplay between these genes may have an effect on antimicrobial resistance in Acinetobacter spp.

Irofulven as first line therapy in recurrent or metastatic gastric cancer: a phase II multicenter study by the Cancer Therapeutics Research Group (CTRG).

BACKGROUND: The purpose of this study was to evaluate the tolerability and efficacy of irofulven, a DNA interacting acylfulvene analog, as first line therapy for patients with recurrent or metastatic gastric cancer. PATIENTS AND METHODS: Twenty-three patients with recurrent or metastatic gastric cancer received irofulven at a dose of 0.45 mg/kg administered intravenously over 30-min infusion (up to a maximum of 50 mg), on days 1 and 8, every 3 weeks. RESULTS: The median number of cycles delivered per patient was 2 (range 1-6). Two patients (9%) had >or= 1-week delay in administration of subsequent cycle of chemotherapy. For the day 8 chemotherapy, dose reductions were required in seven patients (30%); dose omitting occurred in five patients (22%). Grade 3/4 anemia and neutropenia occurred in 22 and 17% of patients, respectively. There was no grade 4 thrombocytopenia and no neutropenic fever was observed. Of the 20 evaluable patients, there were no responses observed, 3 patients had stable disease after 2 cycles of treatment which was not confirmed by a further assessment. Median overall survival was 6.05 months (95% CI 4.55-9.39). CONCLUSIONS: Irofulven was tolerated at the dose of 0.45 mg/kg on days 1 and 8, every 3 weeks but showed no evidence of antitumor activity in patients with advanced gastric cancer.

Bispectral index during modified rapid sequence induction using thiopentone or propofol and rocuronium.

This randomized controlled trial compared Bispectral Index (BIS) values in 40 patients after a modified rapid sequence induction using thiopentone 4 mg/kg or propofol 2 mg/kg with rocuronium 0.6 mg/kg as muscle relaxant. Endotracheal intubation was performed at 60 seconds from induction of anaesthesia and BIS values were recorded for three minutes after induction. At the 120, 150 and 180 second measurements there was a significantly greater proportion of subjects with BIS values < or = 60 ("anaesthetized") in the propofol group compared with the thiopentone group (P values < 0.02, < 0.01 and < 0.01 respectively). All intubations were completed within two minutes. No explicit recall of intubation was detected clinically with either induction agent. The BIS scores we have measured suggest that thiopentone 4 mg/kg is more likely to be associated with lighter planes of anaesthesia and consequent risk of awareness than propofol 2 mg/kg, if intubation is delayed or prolonged.

Neoadjuvant chemotherapy in the management of colorectal metastases: A review of the literature.

INTRODUCTION: Five-year survival rates of between 20% and 45% are achievable in patients following hepatectomy for liver metastases from colorectal cancer. Sadly, a great majority of patients present with unresectable liver disease with virtually no long-term survival. This paper reviews the development and role of preoperative chemotherapy in trying to downstage unresectable liver disease. METHODS: The author retrieved most of the citations by performing a PubMed search for studies related to preoperative chemotherapy followed by surgical resection of liver metastases. RESULTS: Larger series have reported resectability rates ranging from 10% to 40% for unresectable colorectal liver metastases after treatment with preoperative chemotherapy. Chemotherapy generally consisted of oxaliplatin added to 5-fluorouracil/leucovorin administered in a chronomodulated fashion. A median of about 5 to 10 months of treatment was necessary for adequate tumour reduction. The 5-year survival rates, after surgery, in completely resected patients were between 30% and 60%. The majority of these patients will relapse, of which half of these will remain confined to the liver. Patients who are able to undergo a repeat hepatectomy may achieve long-term survival rates similar to the initial resection. Preliminary data from a recent study suggest that initial treatment with an oxaliplatin-containing regimen may lead to a higher resectability rate compared to an irinotecan-containing combination (18% versus 7%). Selective intra-arterial infusion has not demonstrated a clear advantage over systemic infusion and, if administered preoperatively, it may even compromise the safety of surgery. CONCLUSIONS: Palliative chemotherapy remains the standard of care for unresectable colorectal liver metastases. However, in carefully selected patients, neoadjuvant chemotherapy may be able to downstage the disease adequately for curative resection.

Toxicity of irinotecan (CPT-11) and hepato-renal dysfunction.

Various clinical and laboratory parameters have been investigated for their ability to predict toxicity arising from the use of the anticancer drug, irinotecan (CPT-11). In particular, patients deficient in the conjugation of SN-38, a metabolite of CPT-11, are known to be at greater risk. We describe one case of a patient with metastatic colorectal cancer treated with a single dose of CPT-11 at 125 mg/m(2). Although this patient lacked any known predictive factors for toxicity, he experienced severe side-effects several days later. We hypothesized that the toxicity in this patient was due to compromised SN-38 conjugation. Plasma samples were analyzed by reversed-phase high-performance liquid chromatography assay for CPT-11 and its metabolites at 96, 144, 168, 192 and 288 h post-administration. We observed that the concentrations of both the parent drug and its metabolites were markedly raised (11- to 60-fold expected). Additionally the estimated terminal half-lives were 1.5-7 times those expected (29.5, 101, 39.6 and 41.8 h for CPT-11, APC, SN-38G and SN-38, respectively). We conclude that the toxicity in this patient was not caused by deficient SN-38 conjugation, but by decreased drug excretion through both hepatic and renal routes.

Transient resonance Raman and density functional theory investigation of the 2-fluorenylnitrenium ion.

We report a transient resonance Raman spectrum for the 2-fluorenylnitrenium ion obtained after photolysis of 2-azidofluorene. The 10 experimental Raman band frequencies of the transient spectrum show very good agreement with the computed frequencies from BPW91/cc-PVDZ density functional theory calculations for the 2-fluorenylnitrenium ion. Our results confirm the assignment of the approximately 460 nm transient absorption band formed after photolysis of 2-azidofluorene in water/acetonitrile or water solution to the singlet ground electronic state 2-fluorenylnitrenium ion. Our study indicates the 2-fluorenylnitrenium has a large degree of iminocyclohexadienyl cation character with significant delocalization of the charge over both phenyl rings of the fluorene moiety. We compare our results for the 2-fluoreneylnitrenium ion to those previously reported for several other arylnitrenium ions.

Transient-resonance Raman and density functional theory investigation of 4-biphenylylnitrenium, 2-fluorenylnitrenium, and diphenylnitrenium ions.

We present transient-resonance Raman spectra for the 4-biphenylylnitrenium, diphenylnitrenium, and 2-fluorenylnitrenium ions. These spectra display a number of fundamental vibrational bands whose frequencies exhibit good agreement with those computed using BPW91/cc-PVDZ density functional theory calculations for the singlet ground states of the 4-biphenylylnitrenium, diphenylnitrenium, and 2-fluorenylnitrenium ions. Comparison of these arylnitrenium ions with each other and with previous results for structurally similar biphenyl radical cations indicates that the degree of iminocyclohexadienyl character observed in these arylnitrenium ions depends on the relative orientation of the two phenyl rings, the nature of the nitrenium ion moiety, and the ability of the biphenyl-like group to accommodate positive charge through formation of a more planar-like structure with quinoidal-like character.

Rapid mycobacterial tuberculosis detection in bronchoalveolar lavage samples by polymerase chain reaction in patients with upper lobe infiltrates and bronchiectasis.

In areas where tuberculosis is endemic, a positive sputum acid-fast bacilli (AFB) smear is frequently regarded as almost diagnostic of pulmonary tuberculosis (PTB). The main problem arises when the AFB smear is negative. The main aim of this study was to determine the clinical utility of rapid mycobacterial tuberculosis (MTB) detection in bronchoalveolar lavage (BAL) samples by polymerase chain reaction (PCR) in 52 patients who underwent diagnostic bronchoscopy for suspected PTB. These patients had either upper lobe infiltrates (n = 31) or bronchiectasis (n = 21). Mycobacterial culture is usually used as the gold standard of diagnosis. We chose to define active PTB based on positive mycobacterial cultures and/or histological evidence of caseous necrosis and AFB, and/or when there was clinical plus radiological improvement following therapy. We compared AFB smear, respiratory mycobacterial culture, BAL PCR for MTB and clinical active PTB. Four patients who were smear and culture negative had clinical and radiological clearance following anti-tuberculous therapy showing that using mycobacterial culture as a gold standard may have its limitations. When Kappa (a chance-corrected measure of agreement) was calculated for acid-fast bacilli smear and BAL PCR against our definition of active PTB, it was 0.28 (fair agreement) and 0.73 (substantial agreement), respectively. BAL PCR gave a sensitivity, specificity, positive and negative predictive values of 66.7%, 100%, 100% and 88%, respectively, for the group with upper lobe infiltrates. We also demonstrated that BAL for PCR has a good concordance with the final diagnosis of active tuberculosis.