The impact of antibiotic resistance on the rampant spread of infectious diseases in Pakistan: Insights from a narrative review.

Background and Aims: Antibiotic resistance (ABR) is a global public health emergency which has seen an uptick in low- to middle-income countries in recent times due to a plethora of aggravating factors and has led to a whole host of setting-specific pathogens registering high rates of resistance, causing outbreaks with graver mortality and morbidity. This review analyzes available literature to determine the causes and effects of ABR and recommend solutions to the problem in a Pakistani setting. Methods: Sources for this narrative review were identified via electronic databases using keyword search methods. The information was retrieved using databases such as PubMed and Science Direct. Additionally, websites such as CDC and World Health Organization were used to attain pertinent information. All the sources were selected as per their relevance and appropriateness toward the purpose of this review. Results: This review details the causes by dividing them into three primary strata, namely (1) under-regulation, (2) over-prescription and self-medication, and (3) lack of medical stewardship. This is made much graver when the COVID-19 pandemic and the subsequent erratic treatment response is considered, with the pandemic augmenting already high levels of consumption. These factors have led a cascade of effects including, but not limited to, a considerable increase in ABR in pathogens to first-line drugs. Conclusion: ABR is a serious and growing issue which will result in undesirable personal, local, and national consequences if unchecked. Mitigation and reversal of this trend is necessary by developing existing programs and investing in novel therapies and pharmaceutical research and strengthening regulatory policies and mechanisms.

Awake craniotomies in South America: Advancements, challenges, and future prospects.

BACKGROUND: Awake craniotomy has emerged as an advanced surgical technique, characterized by keeping the patient awake during brain surgery. In South America, awake craniotomies have grained traction in neurosurgical practices across various medical centres and hospitals, with notable practitioners contributing to its growth and refinement in the region. PURPOSE: This study aims to explore the integration and impact of awake craniotomies in South American neurosurgical practices. The focus is on understanding the benefits, challenges, and potential transformative effects of the procedure in the region. RESEARCH DESIGN: A comprehensive narrative review and analysis through a thorough examination of the existing literature. RESULTS: The findings indicate that awake craniotomies in South America offer substantial benefits, including cost savings thorugh reduced hospitalization time, quicker recovery and decreased morbidity. Enhanced safety, effective pain management and reduced anaesthesia also contribute to this. CONCLUSION: Whilst the adaptation of awake craniotomies in South America holds great promise in transforming neurosurgical care in the region, significant challenges hinder its widespread adoption. Inadequate infrastructure, limited access to equipment, financial instability, and shortages in trained healthcare providers represent challenges that need to be addressed.

Topical Diclofenac to Manage Opioid-Refractory Pain in a Rare Pancreatic Fibrosarcoma.

Pancreatic cancer is often diagnosed at an advanced stage and is frequently associated with severe pain. Traditional pain management in this condition may be improved with the use of topical diclofenac. A 39-year-old man with advanced pancreatic fibrosarcoma metastatic to the thoracic spine presented to the hospital with severe abdominal pain refractory to escalating doses of opioids. A celiac plexus block produced significant, yet inadequate, pain reduction. Satisfactory pain control and opioid de-escalation were ultimately achieved with the application of topical diclofenac gel to an area of bony metastasis. This case illustrates the potential for pain control using topical diclofenac in patients with pancreatic soft tissue tumors and vertebral metastases. Topical diclofenac may exert antitumoral effects and targeted application may improve absorption, leading to improved pain control. The use of topical diclofenac for pain management in metastatic pancreatic cancer presents an interesting tool that should be considered in similar cases.

A 3-year analysis of the impact of COVID-19 pandemic on NSTEMI incidence, clinical characteristics, management, and outcomes.

OBJECTIVE: The COVID-19 pandemic has been associated with decreased incidence of acute coronary syndrome with worsened outcomes. Few studies have addressed the effects beyond the initial phases of the pandemic. This study elucidated the incidence, clinical characteristics, management, and outcomes of NSTEMI at a tertiary referral center from sample time periods of 2019-2022. METHODS: This study included consecutive NSTEMI patients from March 14-May 9, 2019-2022. Variables included baseline characteristics, clinical features on arrival, management strategy, time parameters, and adverse outcomes. The primary outcome was defined as death, heart failure requiring diuretics, and/or sustained ventricular arrhythmia. RESULTS: This study comprised 250 patients of whom 181 who were admitted during the COVID-19 outbreak. Baseline characteristics were similar among groups. There was a reduction in door-to-angiography time from 29 h in 2019 to 19 h in 2020 [p = 0.01] and 20 h in 2021 [p = 0.02]. PCI intervention increased from 31.8% in 2019% to 50.0% in 2020 [p = 0.05] and 54.7% in 2021 [p < 0.01]. Median length-of-stay (LOS) was reduced from 3 days in 2019 to 2 days in 2020 [p = 0.03]. There was no significant change in outcomes in COVID-19 cohorts compared to control year. CONCLUSIONS: NSTEMI patients during the first 2 years of the COVID-19 pandemic were associated with reduced door-to-angiography times and increased percutaneous coronary intervention (PCI), and patients in year one were associated with reduced LOS. This study suggests that NSTEMI may be managed more efficiently thus reducing hospital bed utilization and potential costs.

Electrical Storm in a Patient with Brugada Syndrome and Coronavirus Disease 2019.

Brugada syndrome (BrS) is an inherited arrhythmia syndrome characterized by right bundle branch block and dynamic ST-segment changes in precordial leads V1-V3. In patients with BrS, fever is a known trigger that may induce arrhythmia. For patients with BrS who contract coronavirus disease 2019 (COVID-19), the inflammatory response poses the risk of causing ventricular arrhythmias. The following case discusses the management of a patient with BrS presenting with electrical storm after contracting COVID-19. Treatment should be focused on aggressive anti-pyretic management along with concomitant pharmacological therapy.

Impact of prostheses on quality of life and functional status of transfemoral amputees in Tanzania.

BACKGROUND: The rise of diabetes and traumatic injury has increased limb loss-related morbidity in low- and middle-income countries (LMICs). Despite this, the majority of amputees in LMICs have no access to prosthetic devices, and the magnitude of prosthesis impact on quality of life (QOL ) and function has not been quantified. OBJECTIVES: Quantify the impact of prostheses on QOL and function in Tanzanian transfemoral amputees. METHOD: A prospective cohort study was conducted. Transfemoral amputees at Muhimbili Orthopaedic Institute were assessed twice before and three times after prosthetic fitting using EuroQol-5D-3L (EQ-5D-3L), Prosthetic Limb Users Survey of Mobility (PLUS-M), 2-minute walk test (2MWT) and Physiologic Cost Index (PCI). Data were analysed for change over time. Subgroup analysis was performed for amputation aetiology (vascular or non-vascular) and prosthesis use. RESULTS: Amongst 30 patients, EQ-5D, PLUS-M and 2MWT improved after prosthesis provision (p < 0.001). EuroQol-5D increased from 0.48 to 0.85 at 1 year (p < 0.001). EuroQol-5D and 2MWT were higher in non-vascular subgroup (p < 0.030). At 1-year, 84% of non-vascular and 44% of vascular subgroups reported using their prosthesis (p = 0.068). CONCLUSION: Prosthesis provision to transfemoral amputees in an LMIC improved QOL and function. This benefit was greater for non-vascular amputation aetiologies. Quality of life and function returned to pre-prosthesis levels with discontinued use of prosthesis.

A study protocol for a Pilot Masked, Randomized Controlled Trial Evaluating Locally-applied Gentamicin versus Saline in Open Tibia Fractures (pGO-Tibia) in Dar es Salaam, Tanzania.

BACKGROUND: Open tibia fractures are a major source of disability in low- and middle-income countries (LMICs) due to the high incidence of complications, particularly infection and chronic osteomyelitis. One proposed adjunctive measure to reduce infection is prophylactic local antibiotic delivery, which can achieve much higher concentrations at the surgical site than can safely be achieved with systemic administration. Animal studies and retrospective clinical studies support the use of gentamicin for this purpose, but no high-quality clinical trials have been conducted to date in high- or low-income settings. METHODS: We describe a protocol for a pilot study conducted in Dar es Salaam, Tanzania, to assess the feasibility of a single-center masked randomized controlled trial to compare the efficacy of locally applied gentamicin to placebo for the prevention of fracture-related infection in open tibial shaft fractures. DISCUSSION: The results of this study will inform the design and feasibility of a definitive trial to address the use of local gentamicin in open tibial fractures. If proven effective, local gentamicin would be a low-cost strategy to reduce complications and disability from open tibial fractures that could impact care in both high- and low-income countries. TRIAL REGISTRATION: ClinicalTrials.gov, Registration # NCT03559400 ; Registered June 18, 2018.

Intramedullary Nailing Versus External Fixation in the Treatment of Open Tibial Fractures in Tanzania: Results of a Randomized Clinical Trial.

BACKGROUND: Open tibial fractures are common injuries in low and middle-income countries, but there is no consensus regarding treatment with intramedullary nailing versus external fixation. The purpose of the present study was to compare the outcomes of initial treatment with intramedullary nailing or external fixation in adults with open tibial fractures. METHODS: We conducted a randomized clinical trial (RCT) at a tertiary orthopaedic center in Tanzania. Adults with acute diaphyseal open tibial fractures were randomly assigned to statically locked, hand-reamed intramedullary nailing or uniplanar external fixation. The primary outcome was death or reoperation for the treatment of deep infection, nonunion, or malalignment. Secondary outcomes included quality of life as measured with the EuroQol-5 Dimensions (EQ-5D) questionnaire, radiographic alignment, and healing as measured with the modified Radiographic Union Scale for Tibial fractures (mRUST). RESULTS: Of the 240 patients who were enrolled, 221 (92.1%) (including 111 managed with intramedullary nailing and 110 managed with external fixation) completed 1-year follow-up. There were 44 primary outcome events (with rates of 18.0% and 21.9% in the intramedullary nailing and external fixation groups, respectively) (relative risk [RR] = 0.83 [95% confidence interval (CI), 0.49 to 1.41]; p = 0.505). There was no significant difference between the groups in terms of the rate of deep infection. Intramedullary nailing was associated with a lower risk of coronal malalignment (RR = 0.11 [95% CI, 0.01 to 0.85]; p = 0.01) and sagittal malalignment (RR = 0.17 [95% CI, 0.02 to 1.35]; p = 0.065) at 1 year. The EQ-5D index favored intramedullary nailing at 6 weeks (mean difference [MD] = 0.07 [95% CI = 0.03 to 0.11]; p < 0.001), but this difference dissipated by 1 year. Radiographic healing (mRUST) favored intramedullary nailing at 6 weeks (MD = 1.2 [95% CI = 0.4 to 2.0]; p = 0.005), 12 weeks (MD = 1.0 [95% CI = 0.3 to 1.7]; p = 0.005), and 1 year (MD = 0.8 [95% CI = 0.2 to 1.5]; p = 0.013). CONCLUSIONS: To our knowledge, the present study is the first RCT assessing intramedullary nailing versus external fixation for the treatment of open tibial fractures in sub-Saharan Africa. Differences in primary events were not detected, and only coronal alignment significantly favored the use of intramedullary nailing. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Practice Patterns for Management of Pediatric Femur Fractures in Low- and Middle-Income Countries.

BACKGROUND: Femoral shaft fractures in children are common in low and middle income countries. In high-income countries, patient age, fracture pattern, associated injuries, child/family socioeconomic status, and surgeon preference dictate fracture management. There is limited literature on treatment patterns for pediatric femur fractures in resource-limited settings. This study surveys surgeons from low (LIC), lower-middle (LMIC), and upper-middle income (UMIC) countries regarding treatment patterns for pediatric femur fractures. METHODS: Surgeons completed an electronic survey reporting surgeon demographics and treatment preference for pediatric femur fractures. Treatment preferences and indications for treatment were separated into 4 groups: infant (0 to 6 mo); toddler (7 mo to 4 y); child (5 to 12 y); adolescent (12 to 17 y). The survey was available in English, Spanish, and French. Analysis was completed with t test and χ test for continuous and categorical variables, respectively, and weighted Pearson correlation (P<0.05). RESULTS: Survey respondents consisted of 413 surgeons from 83 countries (20 LIC, 33 LMIC, 30 UMIC). The majority of respondents were fellowship trained (83%) most commonly in pediatrics (26%) and trauma (43%). Most treated >10 pediatric femur fractures per year (68%). Respondents reported treating infant femur fractures nonoperatively using Pavlik harness (19%), spica cast (60%), or traction with delayed spica cast (14%). Decreasing socioeconomic status was associated with higher nonoperative treatment rate in toddlers, children, and adolescents. Respondents commonly utilize bed rest and traction for child femur fractures in LICs (63%) and LMICs (65%) compared with UMICs (35%) (UMIC vs. LMIC P<0.001; UMIC vs. LIC P<0.001). Surgeries in children more commonly involve open reduction with internal fixation (UMIC 19%, LMIC 33%, LIC 40%; P<0.05 between UMIC-LMIC and UMIC-LIC). CONCLUSION: This is one of the largest surveys describing treatment patterns for pediatric femur fractures in low and middle income countries. Differences are evident including lower operative treatment rate in younger children and lower intramedullary fixation rates in older children. Future studies should investigate the value of treatment options in resource-limited settings. LEVEL OF EVIDENCE: Level II-prospective comparative study.

Barriers to Performing Soft Tissue Reconstruction Procedures among Orthopedic Surgeons in Low- and Middle-income Countries: Results of a Surgical Skills Training Course.

BACKGROUND: Appropriate management of soft tissue injury associated with orthopedic trauma is challenging in low- and middle-income countries (LMICs) due to the lack of available reconstructive surgeons. The Surgical Management and Reconstructive Training (SMART) course teaches orthopedic surgeons reconstructive techniques aimed at improving soft tissue management. This study aims to identify additional barriers to implementing these techniques for surgeons in LMICs who have attended SMART courses. METHODS: This is a mixed-methods study including a Likert-scale-based survey administered to 150 surgeons from LMICs attending the 2018 SMART courses in Tanzania and San Francisco and key informant interviews with 20 surgeons who perform soft tissue coverage procedures. RESULTS: In surveys, respondents reported inadequate local plastic surgeon availability for lower extremity fracture requiring muscle flaps (88%). Surgeons agreed that flap surgeries are important for patients with significant soft tissue injury following open fractures (97%). They reported inadequate access to instruments, such as dermatomes (59%) and Humby knives (32%), and senior-level support (31%). Fewer than half of surgeons with flap experience (n = 85) felt confident in training peers (45%). In interviews, delays in returning patients to operating rooms were frequently cited as a barrier (90%). CONCLUSIONS: Our study demonstrates that soft tissue procedures are perceived as a high priority among orthopedic surgeons, but there are multiple barriers, including a lack of plastic surgeons, and many modifiable barriers including a lack of surgical equipment, peer training, and senior colleague support.

Orthopaedic Trauma in Low-resource Settings: Measuring Value.

There is increasing recognition of both the impact and value of trauma care in low- and middle-income countries (LMICs). However, data supporting the value of musculoskeletal trauma care specifically are lacking. This review discusses methods of economic analysis relevant to low-resource settings and provides a review of cost studies related to orthopaedic trauma care in these settings. In general, microcosting methods are preferred in LMICs because of the lack of databases with aggregate cost data. It is important that studies use a societal perspective that includes the indirect costs of treatment in addition to direct costs of medical care. Cost-effectiveness studies most commonly report cost per disability-adjusted life year, particularly in LMICs, but quality-adjusted life years are an acceptable alternative that is based on more empiric data. There are solid economic data supporting potential cost savings and improved outcomes with intramedullary nailing for femoral shaft fractures. Trauma care hospitals and educational initiatives have also been found to be highly cost-effective. However, very little data exist to support other interventions in orthopaedic trauma. Orthopaedic surgeons should strive to understand these methodologies and support the conduct of rigorous economic analysis to better establish the value of musculoskeletal trauma care in LMICs.

Identification of human short introns.

Canonical pre-mRNA splicing requires snRNPs and associated splicing factors to excise conserved intronic sequences, with a minimum intron length required for efficient splicing. Non-canonical splicing-intron excision without the spliceosome-has been documented; most notably, some tRNAs and the XBP1 mRNA contain short introns that are not removed by the spliceosome. There have been some efforts to identify additional short introns, but little is known about how many short introns are processed from mRNAs. Here, we report an approach to identify RNA short introns from RNA-Seq data, discriminating against small genomic deletions. We identify hundreds of short introns conserved among multiple human cell lines. These short introns are often alternatively spliced and are found in a variety of RNAs-both mRNAs and lncRNAs. Short intron splicing efficiency is increased by secondary structure, and we detect both canonical and non-canonical short introns. In many cases, splicing of these short introns from mRNAs is predicted to alter the reading frame and change protein output. Our findings imply that standard gene prediction models which often assume a lower limit for intron size fail to predict short introns effectively. We conclude that short introns are abundant in the human transcriptome, and short intron splicing represents an added layer to mRNA regulation.

Reducing clinical MRI motion degradation using a prescan patient information pamphlet.

OBJECTIVE: Voluntary patient motion is a common cause of image degradation during MRI and leads to repeated scanning, decreasing efficiency, and increasing costs. We hypothesized that providing an educational pamphlet to patients before their MRI examination could improve image quality and decrease the number of repeated sequences needed because of motion artifacts. SUBJECTS AND METHODS: Over 12 months, we recruited patients undergoing MRI for any neurologic condition. The control group received a routine safety questionnaire concerning MRI scanning. The intervention group was given an additional pamphlet describing the examination and graphically emphasizing the value of remaining still during scanning; comprehension was confirmed by questionnaire. The radiology technologists performing the examinations were blinded to group assignments; they recorded the number of repeated sequences needed because of motion artifacts and assessed image quality on a scale of 0 to 4 (0 = unusable, 4 = perfect). RESULTS: The number of patients requiring repeated MRI sequences (control group vs intervention group: 40 vs 20, respectively; p = 0.009) and the total number of repeated MRI sequences (52 vs 27, p = 0.004) decreased in the group who read the pamphlet compared with the control group. CONCLUSION: Providing a simple educational pamphlet to patients before their MRI examinations that illustrated motion degradation and emphasized the need to remain still significantly reduced the number of repeated sequences deemed necessary by the MRI technologist.

Fluoroquinolones inhibit HCV by targeting its helicase.

BACKGROUND: HCV has infected >170 million individuals worldwide. Effective therapy against HCV is still lacking and there is a need to develop potent drugs against the virus. In the present study, we have employed two culture models to test the activity of fluoroquinolone drugs against HCV: a subgenomic replicon that is able to replicate independently in the cell line Huh-8 and the Huh-7 cell culture model that employs cells transfected with synthetic HCV RNA to produce the infectious HCV particles. Fluoroquinolones have also been shown to have inhibitory activity against certain viruses, possibly by targeting the viral helicase. To tease out the mechanism of the antiviral activity of fluoroquinolones, their effect on HCV NS3 helicase protein was also tested. METHODS: Huh-7 cells producing the HCV virion as well as Huh-8 cells were grown in the presence or absence of 12 different fluoroquinolones. Afterwards, Huh-7 and Huh-8 cells were lysed and viral RNA was extracted. The extracted RNA was reverse transcribed and quantified by real-time quantitative PCR. Fluoroquinolones were also tested on purified NS3 protein in a molecular-beacon-based in vitro helicase assay. RESULTS: To varying degrees, all of the tested fluoroquinolones effectively inhibited HCV replication in both Huh-7 and Huh-8 culture models. The inhibition of HCV NS3 helicase activity was also observed with all 12 of the fluoroquinolones. CONCLUSIONS: Fluoroquinolones inhibit HCV replication possibly by targeting the HCV NS3 helicase. These drugs hold promise for the treatment of HCV infection.

Wrist drop: an atypical presentation of renal cell carcinoma.

Renal cell carcinoma (RCC) causing metastasis to the skeletal muscles is extremely rare. The authors describe a patient with history of RCC treated 5 years ago with radical nephrectomy who presented with left arm swelling after receiving seasonal flu shot. He was initially diagnosed with cellulitis, treated with intravenous antibiotics and discharged home. One month later, he presented with persistent left arm swelling accompanied by wrist drop. Subsequently he developed increased swelling, decreased pulse and wrist drop. He was diagnosed with compartment syndrome, for which fasciotomy was performed, and tissue samples were sent for analysis. Histopathological analysis confirmed metastatic clear cell RCC. The authors described a literature review of previously described cases of metastasis of renal cell cancer to the skeletal muscles. The authors also discussed the rarity of muscle metastasis and unpredictable behavior of RCC after being dormant for long periods.

The spread of HIV in Pakistan: bridging of the epidemic between populations.

In the last two decades, 'concentrated epidemics' of human immunodeficiency virus (HIV) have established in several high risk groups in Pakistan, including Injecting Drug Users (IDUs) and among men who have sex with men (MSM). To explore the transmission patterns of HIV infection in these major high-risk groups of Pakistan, 76 HIV samples were analyzed from MSM, their female spouses and children, along with 26 samples from a previously studied cohort of IDUs. Phylogenetic analysis of HIV gag gene sequences obtained from these samples indicated a substantial degree of intermixing between the IDU and MSM populations, suggesting a bridging of HIV infection from IDUs, via MSM, to the MSM spouses and children. HIV epidemic in Pakistan is now spreading to the female spouses and offspring of bisexual MSM. HIV control and awareness programs must be refocused to include IDUs, MSM, as well as bisexual MSM, and their spouses and children.

Patterns of HIV infection among native and refugee Afghans.

The current study was conducted to explore the origins of the HIV epidemics among the Afghan refugees in Pakistan and the native Afghans in Afghanistan. Phylogenetic analysis of HIV gag gene from 40 samples showed diverse HIV variants, originating from a number of countries. Intermixing of diverse HIV variants among Afghans may give rise to seeding of infections with rare HIV strains which may pose serious challenges for the treatment and control of infection.